US11629190B2 - Canine antibody therapeutic for treating cancer - Google Patents
Canine antibody therapeutic for treating cancer Download PDFInfo
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- US11629190B2 US11629190B2 US16/992,412 US202016992412A US11629190B2 US 11629190 B2 US11629190 B2 US 11629190B2 US 202016992412 A US202016992412 A US 202016992412A US 11629190 B2 US11629190 B2 US 11629190B2
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- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
Definitions
- V H H single heavy chain variable
- PD-1 programmed death
- PD-1 (also known as, PDCD1 or CD279) is a protein expressed on the surface of some immune cells, including T cells and is involved in regulating immune responses to tissues and cells of the body. Binding of PD-1 cognate ligands (e.g. a PD-1-ligand (PD-L), such as PD-L1 and PD-L2) expressed on normal cells and tissues can induce a state of self-tolerance by triggering a signal to suppress potential “self-reactive” T cell killing activity and prevent autoimmune disease. However, some tumor cells also express large amounts of PD-L1, thereby evading T cell killing and promoting tumor growth and metastasis.
- PD-L PD-1-ligand
- Antibodies that disrupt the binding of PD-1 to anti-tumor T Cells, or to PD-L1 expressed on tumor cells, can reinvigorate exhausted T cells, thereby abrogating the immune suppressive activity of tumor cells and allow the body's immune system to control and or eliminate cancer disease.
- Cancer is the leading cause of death for over 80% of dog breeds and all mix-breed dogs. This equates to cancer killing nearly 30% of all dogs each year (Fleming et al., Journal of Veterinary Internal Medicine, 25(2): p. 187-198, 2011).
- primary cancer treatments for dogs are limited to older therapies used at clinically lower doses resulting in inferior outcomes compared to humans (Gustafson, D. L., et al., Pharmacol Ther, Pharmacol Ther, 188:80-96, 2018.
- therapies that augment immune cell activity have been shown to control and eradicate human cancers, establishing these immunotherapies as an effective first-line treatment of cancer (Niyongere et al. J. Thorac Dis 10(Suppl 3): p. 5433-s450, 2018; Carretero-Gonzalez, A., et al., Oncotarget 9(9): p. 8706-8715, 2018.
- PD-1 One immune target in cancer treatment is PD-1 (Ahmadzadeh et al., Blood, 114(8): p. 1537-1544, 2009).
- Two monoclonal antibodies that function therapeutically through the blockade of PD-1/PD-L1 in human cancer patients have been approved by the US Food and Drug Administration, KEYTRUDA® and OPDIVO®. Both have shown to restore the tumor-eradicating immune responses, improve survival, and have cured a number of patients (Carretero-Gonzalez et al., Oncotarget, 9(9): p. 8706-8715, 2018).
- V H H monoclonal antibodies are disclosed that specifically bind to canine PD-1. Antigen binding fragments of these antibodies are also disclosed, as are bispecific antibodies including these V H H monoclonal antibodies.
- V H H monoclonal antibodies, antigen binding fragments thereof, and bispecific antibodies such as for increasing an immune response and/or treating a tumor in a canine subject, for example a dog.
- Methods are also for detecting canine PD-1 in a biological sample from a canine subject.
- FIG. 1 Detection of Canine PD-1 Reactive Alpaca Sera by Western Blot.
- Protein lysates from Cos cells expressing a recombinant 6 ⁇ His-tagged canine PD-1 construct (Cos PD-1) were fractionated on SDS-PAGE electrophoresis gel along with molecular weight markers (Mark) and transferred to nitrocellulose membranes.
- Membranes were separated and incubated with either serum from an alpaca immunized with canine PD-1 DNA vaccine or anti-6 ⁇ His HRP (horse radish peroxidase) antibody conjugate in TBS-tween buffer.
- a secondary anti-camelid antibody-HRP conjugate was used to detect camelid antibody binding. Reactivity of the PD-1 protein was observed at the same molecular mass position in both blots corresponding to PD-1 (*).
- FIG. 2 is Table 1, Results of Analysis of Binding Affinities and Inhibition of PD-1/PD-L1 Binding.
- Nanobody PD-1 binding or blockade of PD-L1 was carried out using antibodies specific for nanobodies or canine PD-L1, respectively.
- Blockade of PD-L1 interactions with PD-1 were determined by signal reduction of bound PD-1 to PD-L1 coated plates with increasing amounts of free nanobody added.
- FIGS. 3 A- 3 B are sequence comparisons of the V H H monoclonal antibody amino acid sequences.
- SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, and 113 are shown (labeled by antibody name).
- the locations of the complementarity determining regions (CDRs) framework regions (FRs) are shown.
- the consensus sequence in FIG. 3 A is SEQ ID NO: 117.
- the top consensus sequence in FIG. 3 B is SEQ ID NO: 118, and the lower consensus sequence is SEQ ID NO: 119.
- the CDR1 is single underlined
- the CDR2 is double underlined
- the CDR3 is italicized.
- FIG. 4 Process for obtaining the V H H domains.
- FIG. 5 PD-1/PD-L1 inhibition by a single nanobody or linked diabody
- nucleic and amino acid sequences listed are shown using standard letter abbreviations for nucleotide bases, and one letter code for amino acids. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand.
- sequence Listing is submitted as an ASCII text file 245-102374-02_Sequence_Listing, Aug. 13, 2020, 53.5 KB, which is incorporated by reference herein. In the accompanying sequence listing:
- the CDR1 is underlined
- the CDR2 is double underlined
- the CDR3 is wiggly underlined.
- SEQ ID NO: 1 is the amino acid sequence of a V H H domain of NAN4 (5A1).
- SEQ ID NO: 2 is the amino acid sequence of the CDR1 of NAN4 (5A1).
- SEQ ID NO: 3 is the amino acid sequence of the CDR2 of NAN4 (5A1).
- SEQ ID NO: 4 is the amino acid sequence of the CDR3 of NAN4 (5A1).
- SEQ ID NO: 5 is the amino acid sequence of a V H H domain of NAN7/8 (5A5).
- SEQ ID NO: 6 is the amino acid sequence of the CDR1 of NAN7/8 (5A5).
- SEQ ID NO: 7 is the amino acid sequence of the CDR2 of NAN7/8 (5A5).
- SEQ ID NO: 8 is the amino acid sequence of the CDR3 of NAN7/8 (5A5).
- SEQ ID NO: 9 is the amino acid sequence of a V H H domain of NAN10 (4B4).
- SEQ ID NO: 10 is the amino acid sequence of the CDR1 of NAN10 (4B4).
- SEQ ID NO: 11 is the amino acid sequence of the CDR2 of NAN10 (4B4).
- SEQ ID NO: 12 is the amino acid sequence of the CDR3 of NAN10 (4B4).
- SEQ ID NO: 13 is the amino acid sequence of a V H H domain of NAN15 (4B2).
- SEQ ID NO: 14 is the amino acid sequence of the CDR1 of NAN15 (4B2).
- SEQ ID NO: 15 is the amino acid sequence of the CDR2 of NAN15 (4B2).
- SEQ ID NO: 16 is the amino acid sequence of the CDR3 of NAN15 (4B2).
- SEQ ID NO: 17 is the amino acid sequence of a V H H domain of NAN28(1B5).
- SEQ ID NO: 18 is the amino acid sequence of the CDR1 of NAN28(1B5).
- SEQ ID NO: 19 is the amino acid sequence of the CDR2 of NAN28(1B5).
- SEQ ID NO: 20 is the amino acid sequence of the CDR3 of NAN28(1B5). The following sequences are shown in FIG. 3 :
- SEQ ID NO: 21 is the amino acid sequence of a V H H domain of NAN 1.
- SEQ ID NOs: 22, 23, and 24 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN1, respectively.
- SEQ ID NO: 25 is the amino acid sequence of a V H H domain of NAN 2.
- SEQ ID NOs: 26, 27, and 28 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN2, respectively.
- SEQ ID NO: 29 is the amino acid sequence of a V H H domain of NAN3.
- SEQ ID NOs: 30, 31 and 32 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN3, respectively.
- SEQ ID NO: 33 is the amino acid sequence of a V H H domain of NAN5.
- SEQ ID NOs: 34, 35 and 36 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN5, respectively.
- SEQ ID NO: 37 is the amino acid sequence of a V H H domain of NAN6.
- SEQ ID NOs: 38, 39 and 40 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN6, respectively.
- SEQ ID NO: 41 is the amino acid sequence of a V H H domain of NAN5.
- SEQ ID NOs: 42, 43 and 44 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN9, respectively.
- SEQ ID NO: 45 is the amino acid sequence of a V H H domain of NAN11.
- SEQ ID NOs: 46, 47 and 48 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN11, respectively.
- SEQ ID NO: 49 is the amino acid sequence of a V H H domain of NAN12.
- SEQ ID NOs: 50, 51 and 52 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN12, respectively.
- SEQ ID NO: 53 is the amino acid sequence of a V H H domain of NAN13.
- SEQ ID NOs: 54, 55 and 56 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN13, respectively.
- SEQ ID NO: 57 is the amino acid sequence of a V H H domain of NAN14.
- SEQ ID NOs: 58, 59 and 60 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN14, respectively.
- SEQ ID NO: 61 is the amino acid sequence of a V H H domain of NAN16.
- SEQ ID NOs: 62, 63 and 64 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN16, respectively.
- SEQ ID NO: 65 is the amino acid sequence of a V H H domain of NAN17.
- SEQ ID NOs: 66, 67, and 68 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN17, respectively.
- SEQ ID NO: 69 is the amino acid sequence of a V H H domain of NAN18.
- SEQ ID NOs: 70, 71 and 72 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN18, respectively.
- SEQ ID NO: 73 is the amino acid sequence of a V H H domain of NAN19.
- SEQ ID NOs: 74, 75 and 76 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN19, respectively.
- SEQ ID NO: 77 is the amino acid sequence of a V H H domain of NAN20.
- SEQ ID NOs: 78, 79 and 80 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN20, respectively.
- SEQ ID NO: 81 is the amino acid sequence of a V H H domain of NAN21.
- SEQ ID NOs: 82, 83, 84 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN21, respectively.
- SEQ ID NO: 85 is the amino acid sequence of a V H H domain of NAN22.
- SEQ ID NOs: 86, 87, and 88 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN22, respectively.
- SEQ ID NO: 89 is the amino acid sequence of a V H H domain of NAN23.
- SEQ ID NOs: 90, 91 and 92 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN23, respectively.
- SEQ ID NO: 93 is the amino acid sequence of a V H H domain of NAN24.
- SEQ ID NOs: 94, 95, 96 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN24, respectively.
- SEQ ID NO: 97 is the amino acid sequence of a V H H domain of NAN25.
- SEQ ID NOs: 98, 99 and 100 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN25, respectively.
- SEQ ID NO: 101 is the amino acid sequence of a V H H domain of NAN26.
- SEQ ID NOs: 102, 103, and 104 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN26, respectively.
- SEQ ID NO: 105 is the amino acid sequence of a V H H domain of NAN27.
- SEQ ID NOs: 106, 107 and 108 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN27, respectively.
- SEQ ID NO: 109 is the amino acid sequence of a V H H domain of NAN29.
- SEQ ID NOs: 110, 111 and 112 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN29, respectively.
- SEQ ID NO: 113 is the amino acid sequence of a V H H domain of NAN30.
- SEQ ID NOs: 114, 115 and 116 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN30, respectively.
- SEQ ID NOs: 117-119 are consensus sequences of a V H H domain of a monoclonal antibody that specifically binds canine PD-1.
- anti-drug antibodies are long lived, reduces the efficacy of the drug greatly increases the risk of adverse reaction to both subsequent treatments Mab drug as well as other immunotherapy that utilize the same Mab platform.
- these drugs are specific to human PD-1, and cannot be used in veterinary subjects.
- mAbs have a molecular weight of 150-160 kDa.
- VHH antibodies are also referred to as “nanobodies,” are small antibody-like molecules, with a molecular weight of 12-15 kDa.
- Camelids (alpaca, llamas and camels) and cartilaginous fishes naturally produce nanobodies that are a peptide chain of ⁇ 110 amino acids that exhibit similar affinity to target (drug-like targeting properties) as the much larger Mab.
- These nanobodies include only a single heavy chain variable (V H H) domain with three complementarity determining regions (CDRs). There are unique properties of these nanobodies, as they are heat-, detergent-, urea- and acid-resistant.
- V H H monoclonal antibodies have superior solubility and permeability of tissues and tumors, short plasma half-life and renal elimination. Furthermore, these V H H monoclonal antibodies do not trigger the complement system that can result in cytotoxicity. Therefore, the safety profile of these V H H monoclonal antibodies disclosed herein is superior and can reduce adverse events and limit reactions that result from the extended half-life of a Mab.
- the disclosed V H H monoclonal antibodies and antigen binding fragments thereof also bind canine PD-1 with a high affinity.
- an antigen includes single or plural antigens and can be considered equivalent to the phrase “at least one antigen.”
- the term “comprises” means “includes.” It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described herein. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. To facilitate review of the various embodiments, the following explanations of terms are provided:
- Administration The introduction of a composition into a subject by a chosen route.
- Administration can be local or systemic.
- the composition such as a composition including a disclosed V H H monoclonal antibody or antigen binding fragment, etc.
- routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), sublingual, rectal, transdermal (for example, topical), intranasal, vaginal, and inhalation routes.
- Agent Any substance or any combination of substances that is useful for achieving an end or result; for example, a substance or combination of substances useful for inhibiting tumor growth or metastasis in a subject.
- Agents include V H H monoclonal antibodies, antigen binding fragments thereof, other proteins, nucleic acid molecules, compounds, small molecules, organic compounds, inorganic compounds, or other molecules of interest.
- An agent can include a therapeutic agent (such as a chemotherapeutic agent), a diagnostic agent or a pharmaceutical agent. The skilled artisan will understand that particular agents may be useful to achieve more than one result.
- Amino acid substitutions The replacement of one amino acid in a polypeptide with a different amino acid or with no amino acid (i.e., a deletion).
- an amino acid in a polypeptide is substituted with an amino acid from a homologous polypeptide, for example, and amino acid in a V H H monoclonal antibody that specifically binds canine PD-1 or antigen binding fragment thereof can be substituted with the corresponding amino acid from another V H H monoclonal antibody that specifically binds canine PD-1 or antigen binding fragment thereof.
- Amplification A technique that increases the number of copies of a nucleic acid molecule (such as an RNA or DNA).
- An example of amplification is the polymerase chain reaction, in which a biological sample is contacted with a pair of oligonucleotide primers, under conditions that allow for the hybridization of the primers to a nucleic acid template in the sample.
- the primers are extended under suitable conditions, dissociated from the template, and then re-annealed, extended, and dissociated to amplify the number of copies of the nucleic acid.
- the product of amplification can be characterized by electrophoresis, restriction endonuclease cleavage patterns, oligonucleotide hybridization or ligation, and/or nucleic acid sequencing using standard techniques.
- Other examples of amplification include strand displacement amplification, as disclosed in U.S. Pat. No. 5,744,311; transcription-free isothermal amplification, as disclosed in U.S. Pat. No. 6,033,881; repair chain reaction amplification, as disclosed in PCT Publication No. WO 90/01069; ligase chain reaction amplification, as disclosed in European Patent Publication EP-A-320 308; gap filling ligase chain reaction amplification, as disclosed in U.S. Pat. No. 5,427,930; and NASBATM RNA transcription-free amplification, as disclosed in U.S. Pat. No. 6,025,134.
- Animal Living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds.
- mammal includes both human and non-human mammals, such as camelids.
- subject includes both human and veterinary subjects, such as dogs.
- a “canine” is an animal in the biological family Canidae, and includes domestic dogs, wolves, coyotes, foxes, jackals, and dingoes.
- Antibody A polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or antigen binding fragments thereof, which specifically binds and recognizes an analyte (antigen) such as, but not limited to, canine PD-1.
- Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
- a heavy and the light chain variable domain of an antibody combine to specifically bind the antigen.
- a naturally occurring primate e.g., human
- canine immunoglobulin has heavy (H) chains and light (L) chains interconnected by disulfide bonds.
- ⁇ lambda
- ⁇ kappa
- IgM immunoglobulin
- IgD immunoglobulin
- IgG immunoglobulin
- IgA immunoglobulin
- Antibodies can be class switched.
- a camelid IgG 2 and IgG 3 has only a heavy chain, and no light chain.
- Naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain (see, e.g., Hamers-Casterman et al., Nature, 363:446-448, 1993; Sheriff et al., Nat. Struct. Biol., 3:733-736, 1996).
- antibody proteins obtained from members of the camel and dromedary Camelus bactrianus and Calelus dromaderius ) family including new world members such as llama species ( Lama paccos, Lama glama and Lama vicugna ) have been characterized with respect to size, structural complexity and antigenicity for human subjects.
- IgG antibodies from this family of mammals as found in nature lack light chains, and are thus structurally distinct from the typical four chain quaternary structure having two heavy and two light chains, for antibodies from other animals. See PCT/EP93/02214 (WO 94/04678 published 3 Mar. 1994).
- camelids produce both conventional heterotetrameric antibodies, where variable regions of heavy and light chains combine to form an antigen binding site and that also produce unique heavy-chain antibodies (HCAbs).
- HCAbs consist of only one antigen binding domain named VHH (variable domain of the heavy chain of the HCAbs).
- VHH variable domain of the heavy chain of the HCAbs
- the VHH chain of these homodimeric antibodies are structurally and functionally similar to a Fab fragment of conventional antibodies.
- the structure of the VHH and variability within the sequence of the V domain is localized in three hypervariable regions (HV) surrounded by more conserved framework regions (FR) all coded in the H-locus of the camelid genome.
- HV hypervariable regions
- FR conserved framework regions
- camelid antibodies e.g. IgG 1
- IGHV Light chain locus and the H-locus
- IGHG1 genes Constant heavy 1 (CH1 exon), hinge region and CH2 and CH3 exons.
- IGHV3H Immunoglobulin Heavy Chain Variable Region
- the CH1 exon region is eliminated during RNA Splicing and joined to the VHH to produce homodimeric heavy chain antibodies comprised of only heavy chains containing VHH, hinge and CH2 and CH3 domains.
- VHH single domain VHH
- FRs framework regions
- CDRs complementary determining regions
- Antigen reactive single domain VHH sequences are also known as Nanobody. (Muyldermans, S., 2013 Annu. Rev. BioChem 82:775-797 Nanobodies: Natural Single-Domain Antibodies).
- V H refers to the variable region of an immunoglobulin heavy chain, including that of an antibody fragment.
- V L refers to the variable region of an immunoglobulin light chain, such as in a primate antibody.
- V H H monoclonal antibodies include two constant domains in the Fc and the V H H domain. V H H monoclonal antibodies lack the CH1 domain of conventional (two variable domain) antibodies (Muyldermans, Annu. Rev. Biochem. 2013. 82:775-97, 2013).
- a V H H monoclonal antibody can be an IgG.
- a V H H monoclonal antibody is generally composed of only one polypeptide chain of 15 kDa, includes the V H H domain with the three CDRs, and has antigen-binding capacity.
- heavy (and light) chain variable domains contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs” (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest , U.S. Department of Health and Human Services, 1991).
- CDRs complementarity-determining regions
- the sequences of the framework regions of different light or heavy chains are relatively conserved within a species.
- the framework region of an antibody that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.
- the CDRs are primarily responsible for antigen binding.
- the CDRs are typically referred to as CDR1, CDR2, and CDR3 (from the N-terminus to C-terminus) and are also typically identified by the chain in which the particular CDR is located.
- a heavy chain (H) CDR3 is located in the variable domain of the heavy chain of the antibody in which it is found
- a light chain (L) CDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found.
- Light chain CDRs are sometimes referred to as CDR L1, CDR L2, and CDR L3.
- Heavy chain CDRs are sometimes referred to as CDR H1, CDR H2, and CDR H3.
- V H H monoclonal antibodies have only a heavy chain (no light chain), and thus include only one CDR1, CDR2 and CDR3.
- the CDR3 is primarily responsible for antigen specificity.
- the sequences of the framework regions of different light or heavy chains are relatively conserved within a species.
- the framework region of an antibody that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.
- variable domain includes in an N- to C-direction, the following structural regions: N-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4-C, wherein FR denotes a framework region amino acid sequence and CDR denotes a complementary determining region amino acid sequence (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991).
- the CDR3 comprises a llama CDR3 V H H domain amino acid sequence; and wherein the antibody binds to canine PD-1.
- CDR-H1 residues 31-35
- CDR-H2 residues 50-65
- CDR-H3 residues 95-102
- CDR-H1 comprises residues 26 to 33, as described by a combination of the Kabat numbering system and Chothia's topological loop definition.
- antibodies such as primate antibodies
- the CDRs of the light chain variable domain are located at residues 24-34 (CDR-L1), residues 50-56 (CDR-L2) and residues 89-97 (CDR-L3) according to the Kabat numbering system.
- Lefranc, et al. (“IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev. Comp.
- a “monoclonal antibody” can be an antibody produced by a single clone of B-lymphocytes or by a cell into which the heavy chain gene (and optionally a light chain gene, such as for a primate antibody) of a single antibody have been transfected.
- a “polyclonal” antibody preparation typically includes different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
- the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
- monoclonal antibodies are isolated from a subject.
- Monoclonal antibodies can have conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. (See, for example, Greenfield (Ed.), Antibodies: A Laboratory Manual, 2 nd ed. New York: Cold Spring Harbor Laboratory Press, 2014).
- the V H H monoclonal antibodies can be produced as recombinant monoclonal antibodies or antigen binding fragments in different expression platforms, avoiding the use of hybridomas and mice.
- V H H monoclonal antibodies can be include a heterologous framework region and can be chimeric. In some embodiments, the heterologous framework region is a dog framework region.
- Binding affinity Affinity of an antibody, such as a V H H monoclonal antibody, or antigen binding fragment thereof, for an antigen.
- affinity is calculated by a modification of the Scatchard method described by Frankel et al., Mol. Immunol., 16:101-106, 1979.
- binding affinity is measured by an antigen/antibody dissociation rate.
- a high binding affinity is measured by a competition radioimmunoassay or by Plasmon resonance in a BIOCORE.
- a high binding affinity is at least about 1 ⁇ 10 ⁇ 8 M.
- a high binding affinity is at least about 1.5 ⁇ 10 ⁇ 8 , at least about 2.0 ⁇ 10 ⁇ 8 , at least about 2.5 ⁇ 10 ⁇ 8 , at least about 3.0 ⁇ 10 ⁇ 8 , at least about 3.5 ⁇ 10 ⁇ 8 , at least about 4.0 ⁇ 10 ⁇ 8 , at least about 4.5 ⁇ 10 ⁇ 8 , or at least about 5.0 ⁇ 10 ⁇ 8 M.
- V H H monoclonal antibodies from immune libraries are of good quality.
- Kinetick (k)on and koff rate constants are generally in the range of 10 5 to 10 6 M ⁇ 1 s ⁇ 1 and 10 ⁇ 2 to 10 ⁇ 4 s ⁇ 1 , respectively, such that low nanomolar or even picomolar equilibrium dissociation constants are obtained.
- affinity parameters are excellent for most applications (Muyldermans, Annu. Rev. Biochem. 2013. 82:775-97, 2013).
- Bio sample A sample obtained from a subject.
- Biological samples include all clinical samples useful for detection in subjects, including, but not limited to, cells, tissues, and bodily fluids, such as blood, derivatives and fractions of blood (such as serum), cerebrospinal fluid; as well as biopsied or surgically removed tissue, for example tissues that are unfixed, frozen, or fixed in formalin or paraffin.
- a biological sample is obtained from a subject having or suspected of having a tumor, such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- the biological sample can include T cells.
- Bispecific antibody A recombinant molecule composed of two different antigen binding domains that consequently binds to two different antigenic epitopes.
- Bispecific antibodies include chemically or genetically linked molecules of two antigen-binding domains.
- the antigen binding domains can be linked using a linker.
- the antigen binding domains can be V H H domains, monoclonal antibodies, antigen-binding fragments (e.g., Fab, scFv, ds-scFv), or combinations thereof.
- a bispecific antibody can include one or more constant domains but does not necessarily include a constant domain.
- Bispecific antibodies include diabodies.
- Carcinoma A malignant tumor including transformed epithelial cells.
- carcinomas include adenocarcinoma, squamous cell carcinoma, anaplastic carcinoma and large and small cell carcinoma.
- Chemotherapeutic agent Any chemical agent with therapeutic usefulness in the treatment of diseases characterized by abnormal cell growth.
- chemotherapeutic agents are useful for the treatment of cancer, including osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, and/or a hematologic malignancy.
- a chemotherapeutic agent is an agent of use in treating a carcinoma.
- additional therapeutic agents include microtubule binding agents, DNA intercalators or cross-linkers, DNA synthesis inhibitors, DNA and RNA transcription inhibitors, antibodies, enzymes, enzyme inhibitors, gene regulators, and angiogenesis inhibitors.
- a chemotherapeutic agent is a radioactive compound.
- Other examples include the anti-neoplastic drugs 5-fluorouracil (5-FU) and IRT.
- chemotherapeutic agent of use see for example, Slapak and Kufe, Principles of Cancer Therapy , Chapter 86 in Harrison's Principles of Internal Medicine, 14th edition; Perry et al., Chemotherapy, Ch. 17 in Abeloff, Clinical Oncology 2 nd ed., ⁇ 2000 Churchill Livingstone, Inc; Baltzer, L., Berkery, R. (eds): Oncology Pocket Guide to Chemotherapy, 2nd ed. St. Louis, Mosby-Year Book, 1995; Fischer, D. S., Knobf, M. F., Durivage, H. J. (eds): The Cancer Chemotherapy Handbook, 4th ed.
- Combination chemotherapy is the administration of more than one agent to treat cancer.
- Chimeric antibody An antibody which includes sequences derived from two different antibodies, such as from different species.
- a chimeric antibody includes one or more CDRs and/or framework regions from one llama V H H domains (or monoclonal antibodies) and CDRs and/or framework regions from another llama V H H domain or a V H from a canine antibody.
- Conditions sufficient to form an immune complex Conditions which allow an antibody or antigen binding fragment thereof to bind to its cognate epitope to a detectably greater degree than, and/or to the substantial exclusion of, binding to substantially all other epitopes. Conditions sufficient to form an immune complex are dependent upon the format of the binding reaction and typically are those utilized in immunoassay protocols or those conditions encountered in vivo. See Harlow & Lane, Antibodies, A Laboratory Manual, 2 nd ed. Cold Spring Harbor Publications, New York (2013) for a description of immunoassay formats and conditions. The conditions employed in the methods are “physiological conditions” which include reference to conditions (e.g., temperature, osmolarity, pH) that are typical inside a living mammal or a mammalian cell.
- the intra-organismal and intracellular environment normally lies around pH 7 (e.g., from pH 6.0 to pH 8.0, more typically pH 6.5 to 7.5), contains water as the predominant solvent, and exists at a temperature above 0° C. and below 50° C. Osmolarity is within the range that is supportive of cell viability and proliferation.
- Conjugate A complex of two molecules linked together, for example, linked together by a covalent bond.
- an antibody is linked to an effector molecule such as a label; for example, an antibody that specifically binds to canine PD-1 covalently linked to a label.
- the linkage can be by chemical or recombinant means.
- the linkage is chemical, wherein a reaction between the antibody moiety and the effector molecule has produced a covalent bond formed between the two molecules to form one molecule.
- a peptide linker short peptide sequence
- conjugates can be prepared from two molecules with separate functionalities, such as an antibody and an effector molecule, they are also sometimes referred to as “chimeric molecules.”
- “Conservative” amino acid substitutions are those substitutions that do not substantially affect or decrease a function of a protein, such as the ability of the protein to interact with a target protein.
- a canine PD-1-specific V H H monoclonal antibody can include up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10 conservative substitutions compared to a reference antibody sequence and retain specific binding activity for canine PD-1.
- the term conservative variation also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid.
- Non-conservative substitutions are those that reduce an activity or function of the anti-canine PD-1 V H H monoclonal antibody, or antigen binding fragment thereof, such as the ability to specifically bind to canine PD-1 or bind to a cancer cell expressing canine PD-1. For instance, if an amino acid residue is essential for a function of the protein, even an otherwise conservative substitution may disrupt that activity. Thus, a conservative substitution does not alter the basic function of a protein of interest.
- Placement in direct physical association includes both in solid and liquid form, which can take place either in vivo or in vitro.
- Contacting includes contact between one molecule and another molecule, for example the amino acid on the surface of one polypeptide, such as a peptide, that contacts another polypeptide.
- Contacting can also include contacting a cell for example by placing a polypeptide in direct physical association with a cell.
- Control A reference standard.
- the control is a negative control sample obtained from a healthy patient, such as a canine subject without a tumor.
- the control is a positive control sample obtained from a patient known to have increased T cells that express canine PD-1, or recombinantly produced purified canine PD-1.
- the control is a historical control or standard reference value or range of values (such as a previously tested control sample, such as a group of patients with known prognosis or outcome, or group of samples that represent baseline or normal values).
- a difference between a test sample and a control can be an increase or conversely a decrease.
- the difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference.
- a difference is an increase or decrease, relative to a control, of at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 500%, or greater than 500%.
- tumor growth, volume and/or metastasis is decreased.
- a therapy reduces a tumor (such as the size of a tumor, the number of tumors, the metastasis of a tumor, or combinations thereof), or one or more symptoms associated with a tumor, for example as compared to the response in the absence of the therapy.
- a therapy decreases the size of a tumor, the number of tumors, the metastasis of a tumor, or combinations thereof, subsequent to the therapy, such as a decrease of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. Such decreases can be measured using the methods disclosed herein.
- a “degenerate variant” refers to a polynucleotide encoding a polypeptide (such as an antibody) that includes a sequence that is degenerate as a result of the genetic code. There are 20 natural amino acids, most of which are specified by more than one codon. Therefore, all degenerate nucleotide sequences encoding a peptide are included as long as the amino acid sequence of the peptide encoded by the nucleotide sequence is unchanged.
- Detectable marker A detectable molecule (also known as a label) that is conjugated directly or indirectly to a second molecule, such as an antibody, to facilitate detection of the second molecule.
- the detectable marker can be capable of detection by ELISA, spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as CT scans, MRIs, ultrasound, fiberoptic examination, and laparoscopic examination).
- detectable markers include fluorophores, chemiluminescent agents, enzymatic linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic iron oxide nanocrystals for detection by MRI).
- Detecting To identify the existence, presence, or fact of something.
- Effective amount A quantity of a specific substance sufficient to achieve a desired effect in a subject to whom the substance is administered, such as a therapeutically effective amount, for treatment. For instance, this can be the amount of a VHH monoclonal antibody or antigen binding fragment thereof necessary to inhibit tumor growth and/or metastasis, or to measurably alter outward symptoms of the tumor.
- administration of an effective amount of a disclosed antibody or antigen binding fragment that binds to canine PD-1 can reduce or inhibit an tumor growth, tumor metastasis, or tumor volume by a desired amount, for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of the tumor), as compared to a suitable control.
- the effective amount of an antibody or antigen binding fragment that specifically binds to canine PD-1 that is administered to a subject will vary depending upon a number of factors associated with that subject, for example the overall health and/or weight of the subject.
- An effective amount can be determined by varying the dosage and measuring the resulting response, such as, for example, a reduction in tumor burden.
- Effective amounts also can be determined through various in vitro, in vivo or in situ immunoassays.
- an effective amount encompasses a fractional dose that contributes in combination with previous or subsequent administrations to attaining an effective response.
- an effective amount of an agent can be administered in a single dose, or in several doses, for example daily, during a course of treatment lasting several days or weeks.
- the effective amount can depend on the subject being treated, the severity and type of the condition being treated, and the manner of administration.
- a unit dosage form of the agent can be packaged in an amount, or in multiples of the effective amount, for example, in a vial (e.g., with a pierceable lid) or syringe having sterile components.
- Effector molecule A molecule intended to have or produce a desired effect; for example, a desired effect on a cell to which the effector molecule is targeted. Effector molecules include such molecules as chemical compounds, polypeptides, radioisotopes and small molecules. Non-limiting examples of effector molecules include toxins, chemotherapeutic agents and anti-angiogenic agents. The skilled artisan will understand that some effector molecules may have or produce more than one desired effect. In one example, an effector molecule is the portion of a chimeric molecule, for example a chimeric molecule that includes a disclosed antibody or fragment thereof, that is intended to have a desired effect on a cell to which the chimeric molecule is targeted.
- Epitope An antigenic determinant. These are particular chemical groups or peptide sequences on a molecule that are antigenic, such that they elicit a specific immune response, for example, an epitope is the region of an antigen to which B and/or T cells respond. An antibody can bind to a particular antigenic epitope, such as an epitope on canine PD-1.
- a gene is expressed when its DNA is transcribed into an RNA or RNA fragment, which in some examples is processed to become mRNA.
- a gene may also be expressed when its mRNA is translated into an amino acid sequence, such as a protein or a protein fragment.
- a heterologous gene is expressed when it is transcribed into an RNA.
- a heterologous gene is expressed when its RNA is translated into an amino acid sequence.
- expression is used herein to denote either transcription or translation. Regulation of expression can include controls on transcription, translation, RNA transport and processing, degradation of intermediary molecules such as mRNA, or through activation, inactivation, compartmentalization or degradation of specific protein molecules after they are produced.
- Expression Control Sequences Nucleic acid sequences that regulate the expression of a heterologous nucleic acid sequence to which it is operatively linked. Expression control sequences are operatively linked to a nucleic acid sequence when the expression control sequences control and regulate the transcription and, as appropriate, translation of the nucleic acid sequence.
- Expression control sequences can include appropriate promoters, enhancers, transcription terminators, a start codon (ATG) in front of a protein-encoding gene, splicing signal for introns, maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and a stop codon.
- control sequences is intended to include, at a minimum, components whose presence can influence expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. Expression control sequences can include a promoter.
- a promoter is a minimal sequence sufficient to direct transcription. Also included are those promoter elements which are sufficient to render promoter-dependent gene expression controllable for cell-type specific, tissue-specific, or inducible by external signals or agents; such elements may be located in the 5′ or 3′ regions of the gene. Both constitutive and inducible promoters are included (see for example, Bitter et al., Methods in Enzymology 153:516-544, 1987). For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage lambda, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like may be used.
- promoters derived from the genome of mammalian cells such as metallothionein promoter or from mammalian viruses (such as the retrovirus long terminal repeat; the adenovirus late promoter; the vaccinia virus 7.5K promoter) can be used.
- Promoters produced by recombinant DNA or synthetic techniques may also be used to provide for transcription of the nucleic acid sequences.
- a polynucleotide can be inserted into an expression vector that contains a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host.
- the expression vector typically contains an origin of replication, a promoter, as well as specific nucleic acid sequences that allow phenotypic selection of the transformed cells.
- Expression vector A vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
- An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system.
- Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.
- Fc region The constant region of an antibody excluding the first heavy chain constant domain.
- Fc region generally refers to the last two heavy chain constant domains of IgA, IgD, and IgG, and the last three heavy chain constant domains of IgE and IgM.
- An Fc region may also include part or all of the flexible hinge N-terminal to these domains.
- an Fc region may or may not include the tailpiece, and may or may not be bound by the J chain.
- the Fc region is typically understood to include immunoglobulin domains C ⁇ 2 and C ⁇ 3 and optionally the lower part of the hinge between C ⁇ 1 and C ⁇ 2.
- the human IgG heavy chain Fc region is usually defined to include residues following C226 or P230 to the Fc carboxyl-terminus, wherein the numbering is according to Kabat.
- the Fc region includes immunoglobulin domains C ⁇ 2 and C ⁇ 3 and optionally the lower part of the hinge between C ⁇ 1 and C ⁇ 2.
- Heterologous Originating from a different genetic source.
- a nucleic acid molecule that is heterologous to a cell originated from a genetic source other than the cell in which it is expressed.
- a heterologous nucleic acid molecule encoding a protein, such as an scFv is expressed in a cell, such as a mammalian cell.
- Methods for introducing a heterologous nucleic acid molecule in a cell or organism are well known in the art, for example transformation with a nucleic acid, including electroporation, lipofection, particle gun acceleration, and homologous recombination.
- Host cells Cells in which a vector can be propagated and its DNA expressed.
- the cell may be prokaryotic or eukaryotic.
- the term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. However, such progeny are included when the term “host cell” is used.
- IgG A polypeptide belonging to the class or isotype of antibodies that are substantially encoded by a recognized immunoglobulin gamma gene.
- Immune complex The binding of antibody or antigen binding fragment to antigen forms an immune complex.
- the formation of an immune complex can be detected through conventional methods, for instance immunohistochemistry, immunoprecipitation, flow cytometry, immunofluorescence microscopy, ELISA, immunoblotting (for example, Western blot), magnetic resonance imaging, CT scans, radiography, and affinity chromatography.
- Immune response A response of a cell of the immune system, such as a B cell, T cell, or monocyte, to a stimulus.
- the response is specific for a particular antigen (an “antigen-specific response”).
- an immune response is a T cell response, such as a CD4+ response or a CD8+ response.
- the response is a B cell response, and results in the production of specific antibodies.
- Immunogen A compound, composition, or substance that can stimulate the production of antibodies or a T cell response in an animal, including compositions that are injected or absorbed into an animal, such as canine PD-1 coupled to a carrier.
- An immunogen can be used to produce antibodies, such as those disclosed herein.
- Inhibiting or Treating a Tumor A therapeutic intervention (for example, administration of a therapeutically effective amount of a V H H monoclonal antibody that specifically binds canine PD-1) that reduces a sign or symptom of a tumor. Treatment can also induce remission, such as reducing the size of a tumor. In particular examples, treatment includes inhibiting metastasis.
- the term “reduces” is a relative term, such that an agent reduces a disease or condition if the disease or condition is quantitatively diminished following administration of the agent, or if it is diminished following administration of the agent, as compared to a reference agent. Reducing a sign or symptom refers to any observable beneficial effect of the treatment.
- Reducing a sign or symptom associated with a tumor can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject (such as a subject having a tumor which has not yet metastasized), a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease (for example by prolonging the life of a subject having tumor), a reduction in the number of tumors or the time between removal of a tumor and the reappearance of the tumor, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular tumor.
- a susceptible subject such as a subject having a tumor which has not yet metastasized
- a reduction in severity of some or all clinical symptoms of the disease for example by prolonging the life of a subject having tumor
- a slower progression of the disease for example by prolonging the life of a subject having tumor
- a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a tumor, but has a genetic predisposition to the tumor, or exhibits only early signs, such as a pre-cancerous lesion, for the purpose of decreasing the risk of developing the tumor.
- the term “prevents” does not necessarily mean that an agent completely eliminates the disease or condition, so long as at least one characteristic of the disease or condition is eliminated.
- a composition that reduces or prevents a tumor can, but does not necessarily completely, prevent risk for developing a tumor.
- isolated A biological component (such as a nucleic acid, peptide, protein or protein complex, for example a V H H monoclonal antibody or antigen binding fragment thereof) that has been substantially separated, produced apart from, or purified away from other biological components in the cell of the organism in which the component naturally occurs, that is, other chromosomal and extra-chromosomal DNA and RNA, and proteins.
- isolated nucleic acids, peptides and proteins include nucleic acids and proteins purified by standard purification methods.
- the term also embraces nucleic acids, peptides and proteins prepared by recombinant expression in a host cell, as well as, chemically synthesized nucleic acids.
- An isolated nucleic acid, peptide or protein, for example an antibody can be at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.
- Linker A bi-functional molecule that can be used to link two molecules into one contiguous molecule, for example, to link an effector molecule to an antibody, or a detectable marker to an antibody.
- Non-limiting examples of peptide linkers include glycine-serine linkers.
- conjugating can refer to making two molecules into one contiguous molecule; for example, linking two polypeptides into one contiguous polypeptide, or covalently attaching an effector molecule or detectable marker radionuclide or other molecule to a polypeptide, such as a Vial monoclonal antibody.
- the linkage can be either by chemical or recombinant means.
- “Chemical means” refers to a reaction between the antibody moiety and the effector molecule such that there is a covalent bond formed between the two molecules to form one molecule.
- Nanoantibody or nanobody (Val) A nanobody is comprised of only one polypeptide chain and is considered the smallest known natural domain with full antigen-binding capacity (15 kDa) that includes three CDRs in a V H H domain.
- the DNA encoding the V H H domain may be obtained and modified by genetic engineering to yield a small recombinant protein having high affinity for a target, resulting in a low molecular weight antibody-derived protein known as a camelid “nanoantibody” or “nanobody” due to the small size. See U.S. Pat. No. 5,759,808 issued Jun.
- a V H H antibody includes in an N- to C-direction, the following structural domains regions: N-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4-C, wherein FR denotes a framework region amino acid sequence and CDR denotes a complementary determining region amino acid sequence, and C is the constant domain (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991). These molecules do not include a light chain variable domain (V L ).
- V L light chain variable domain
- Neoplasia is an abnormal growth of tissue or cells that results from excessive cell division. Neoplastic growth can produce a tumor.
- the amount of a tumor in an individual is the “tumor burden” which can be measured as the number, volume, or weight of the tumor.
- a tumor that does not metastasize is referred to as “benign.”
- a tumor that invades the surrounding tissue or can metastasize (or both) is referred to as “malignant.”
- Tumors of the same tissue type are primary tumors originating in a particular organ (such as head and neck, breast, or bladder). Tumors of the same tissue type may be divided into tumors of different sub-types. For examples, lung carcinomas can be divided into adenocarcinomas, small cell, squamous cell, or non-small cell tumors.
- solid tumors such as sarcomas (connective tissue cancer) and carcinomas (epithelial cell cancer)
- sarcomas connective tissue cancer
- carcinomas epidermal cell cancer
- fibrosarcoma myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas
- synovioma mesothelioma
- Ewing's tumor leiomyosarcoma
- rhabdomyosarcoma colorectal carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, head and neck carcinoma, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas,
- hematological tumors include leukemias, including acute leukemias (such as 11q23-positive acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and myelodysplasia.
- acute leukemias such as 11q23-positive acute leukemia, acute lympho
- the lymphoid malignancy can be adult T cell leukemia, cutaneous T cell lymphoma, anaplastic large cell lymphoma, Hodgkin's lymphoma, or a diffuse large B cell lymphoma.
- a tumor is an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, and a hematologic malignancy.
- Nucleic acid A polymer composed of nucleotide units (ribonucleotides, deoxyribonucleotides, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof) linked via phosphodiester bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof.
- nucleotide polymers in which the nucleotides and the linkages between them include non-naturally occurring synthetic analogs, such as, for example and without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like.
- oligonucleotide typically refers to short polynucleotides, generally no greater than about 50 nucleotides. It will be understood that when a nucleotide sequence is represented by a DNA sequence (i.e., A, T, G, C), this also includes an RNA sequence (i.e., A, U, G, C) in which “U” replaces “T.”
- Nucleotide includes, but is not limited to, a monomer that includes a base linked to a sugar, such as a pyrimidine, purine or synthetic analogs thereof, or a base linked to an amino acid, as in a peptide nucleic acid (PNA).
- a nucleotide is one monomer in a polynucleotide.
- a nucleotide sequence refers to the sequence of bases in a polynucleotide.
- nucleotide sequences the left-hand end of a single-stranded nucleotide sequence is the 5′-end; the left-hand direction of a double-stranded nucleotide sequence is referred to as the 5′-direction.
- the direction of 5′ to 3′ addition of nucleotides to nascent RNA transcripts is referred to as the transcription direction.
- the DNA strand having the same sequence as an mRNA is referred to as the “coding strand;” sequences on the DNA strand having the same sequence as an mRNA transcribed from that DNA and which are located 5′ to the 5′-end of the RNA transcript are referred to as “upstream sequences;” sequences on the DNA strand having the same sequence as the RNA and which are 3′ to the 3′ end of the coding RNA transcript are referred to as “downstream sequences.”
- cDNA refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.
- Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
- a gene encodes a protein if transcription and translation of mRNA produced by that gene produces the protein in a cell or other biological system.
- coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings
- non-coding strand used as the template for transcription
- a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.
- a first sequence is an “antisense” with respect to a second sequence if a polynucleotide whose sequence is the first sequence specifically hybridizes with a polynucleotide whose sequence is the second sequence.
- a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence.
- a promoter such as the CMV promoter
- operably linked DNA sequences are contiguous and, where necessary to join two protein-coding regions, in the same reading frame.
- compositions and formulations suitable for pharmaceutical delivery of the disclosed antibodies and antigen binding fragments thereof are conventional. Remington's Pharmaceutical Sciences , by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995, describes compositions and formulations suitable for pharmaceutical delivery of the disclosed antibodies and antigen binding fragments thereof.
- parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like
- solid compositions e.g., powder, pill, tablet, or capsule forms
- conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
- compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
- auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
- suitable for administration to a subject the carrier may be sterile, and/or suspended or otherwise contained in a unit dosage form containing one or more measured doses of the composition. It may also be accompanied by medications for its use for treatment purposes.
- the unit dosage form may be, for example, in a sealed vial that contains sterile contents or a syringe for injection into a subject, or lyophilized for subsequent solubilization and administration or in a solid or controlled release dosage.
- Polypeptide Any chain of amino acids, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation). “Polypeptide” applies to amino acid polymers including naturally occurring amino acid polymers and non-naturally occurring amino acid polymer as well as in which one or more amino acid residue is a non-natural amino acid, for example an artificial chemical mimetic of a corresponding naturally occurring amino acid.
- a “residue” refers to an amino acid or amino acid mimetic incorporated in a polypeptide by an amide bond or amide bond mimetic.
- a polypeptide has an amino terminal (N-terminal) end and a carboxy terminal (C-terminal) end. “Polypeptide” is used interchangeably with peptide or protein, and is used herein to refer to a polymer of amino acid residues.
- Polypeptides and peptides such as the antibodies disclosed herein can be modified by a variety of chemical techniques to produce derivatives having essentially the same activity as the unmodified peptides, and optionally having other desirable properties.
- carboxylic acid groups of the protein may be provided in the form of a salt of a pharmaceutically-acceptable cation or esterified to form a C 1 -C 16 ester, or converted to an amide of formula NR 1 R 2 wherein R 1 and R 2 are each independently H or C 1 -C 16 alkyl, or combined to form a heterocyclic ring, such as a 5- or 6-membered ring.
- Amino groups of the peptide may be in the form of a pharmaceutically-acceptable acid addition salt, such as the HCl, HBr, acetic, benzoic, toluene sulfonic, maleic, tartaric and other organic salts, or may be modified to C 1 -C 16 alkyl or dialkyl amino or further converted to an amide.
- a pharmaceutically-acceptable acid addition salt such as the HCl, HBr, acetic, benzoic, toluene sulfonic, maleic, tartaric and other organic salts
- Hydroxyl groups of the peptide side chains can be converted to C 1 -C 16 alkoxy or to a C 1 -C 16 ester using well-recognized techniques.
- Phenyl and phenolic rings of the peptide side chains can be substituted with one or more halogen atoms, such as F, Cl, Br or I, or with C 1 -C 16 alkyl, C 1 -C 16 alkoxy, carboxylic acids and esters thereof, or amides of such carboxylic acids.
- Methylene groups of the peptide side chains can be extended to homologous C 2 -C 4 alkylenes. Thiols can be protected with any one of a number of well-recognized protecting groups, such as acetamide groups.
- cyclic structures into the peptides of this disclosure to select and provide conformational constraints to the structure that result in enhanced stability.
- a C- or N-terminal cysteine can be added to the peptide, so that when oxidized the peptide will contain a disulfide bond, generating a cyclic peptide.
- Other peptide cyclizing methods include the formation of thioethers and carboxyl- and amino-terminal amides and esters.
- PD-1 A protein that forms a complex with PD-L1 or PD-L2 protein and is involved in an immune response, such as the co-stimulation of T cells.
- PD-1 proteins are substantially identical to the naturally occurring (wild type) PD-1 (see, for example, Ishida et al. EMBO J. 11:3887-3895, 1992, Shinohara et al. Genomics 23:704-706, 1994; and U.S. Pat. No. 5,698,520, all incorporated by reference herein in their entirety).
- Exemplary sequences for canine PD-1 are disclosed, for example, in GENBANK® Accession Nos.
- PD-1 signaling reduces, for example, CD8+ T cell cytoxicity by reducing T cell proliferation or altering cytokine production.
- a PD-1 polypeptide can reduce CD8+ T cell cytotoxic activity by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than 100% below control levels as measured by any standard method.
- the term “activity” with respect to a PD-1 polypeptide or protein includes any activity which is inherent to the naturally occurring PD-1 protein, such as the ability to modulate an inhibitory signal in an activated immune cell, such as by engaging a natural ligand on an antigen presenting cell. Such modulation of an inhibitory signal in an immune cell results in modulation of proliferation and/or survival of an immune cell and/or cytokine secretion by an immune cell.
- PD-1 protein can also modulate a costimulatory signal by competing with a costimulatory receptor for binding of a B7 molecule.
- PD-1 activity includes the ability of a PD-1 polypeptide or protein to bind its natural ligand(s), the ability to modulate immune cell costimulatory or inhibitory signals, and the ability to modulate (decrease) the immune response.
- “Reduce the activity of PD-1” refers to a decrease in the level or biological activity of PD-1 relative to the level or biological activity of PD-1 protein in a control, such as an untreated subject or sample.
- the level or activity is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or even greater than 100%, relative to an untreated control.
- the biological activity of PD-1 protein is reduced if binding of PD-1 protein to PD-L1, PD-L2, or both is reduced, thereby resulting in a reduction in PD-1 signaling and therefore resulting in an increase in CD8+ T cell cytotoxicity.
- purified does not require absolute purity; rather, it is intended as a relative term.
- a purified peptide preparation is one in which the peptide or protein (such as an antibody) is more enriched than the peptide or protein is in its natural environment within a cell.
- a preparation is purified such that the protein or peptide represents at least 50% of the total peptide or protein content of the preparation.
- a recombinant nucleic acid is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination can be accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, for example, by genetic engineering techniques.
- a recombinant protein is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence.
- a recombinant protein is encoded by a heterologous (for example, recombinant) nucleic acid that has been introduced into a host cell, such as a bacterial or eukaryotic cell.
- the nucleic acid can be introduced, for example, on an expression vector having signals capable of expressing the protein encoded by the introduced nucleic acid or the nucleic acid can be integrated into the host cell chromosome.
- Sequence identity The similarity between amino acid sequences is expressed in terms of the similarity between the sequences, otherwise referred to as sequence identity. Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are. Homologs, orthologs, or variants of a polypeptide will possess a relatively high degree of sequence identity when aligned using standard methods.
- the number of matches is determined by counting the number of positions where an identical nucleotide or amino acid residue is present in both sequences.
- 75.11, 75.12, 75.13, and 75.14 are rounded down to 75.1, while 75.15, 75.16, 75.17, 75.18, and 75.19 are rounded up to 75.2.
- the length value will always be an integer.
- NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol. Biol. 215:403, 1990) is available from several sources, including the National Center for Biotechnology Information (NCBI, Bethesda, Md.) and on the internet, for use in connection with the sequence analysis programs blastp, blastn, blastx, tblastn and tblastx. A description of how to determine sequence identity using this program is available on the NCBI website on the internet.
- Homologs and variants of a polypeptide are typically characterized by possession of at least about 75%, for example at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity counted over the full length alignment with the amino acid sequence of interest. Proteins with even greater similarity to the reference sequences will show increasing percentage identities when assessed by this method, such as at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.
- homologs and variants When less than the entire sequence is being compared for sequence identity, homologs and variants will typically possess at least 80% sequence identity over short windows of 10-20 amino acids, and may possess sequence identities of at least 85% or at least 90% or 95% depending on their similarity to the reference sequence. Methods for determining sequence identity over such short windows are available at the NCBI website on the internet. One of skill in the art will appreciate that these sequence identity ranges are provided for guidance only; it is entirely possible that strongly significant homologs could be obtained that fall outside of the ranges provided.
- sequence comparison For sequence comparison of nucleic acid sequences, typically one sequence acts as a reference sequence, to which test sequences are compared.
- test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters are used.
- Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482, 1981, by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443, 1970, by the search for similarity method of Pearson & Lipman, Proc. Nat'l.
- PILEUP can be obtained from the GCG sequence analysis software package, e.g., version 7.0 (Devereaux et al., Nuc. Acids Res. 12:387-395, 1984.
- BLAST Altschul et al., J. Mol. Biol. 215:403-410, 1990 and Altschul et al., Nucleic Acids Res. 25:3389-3402, 1977.
- Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov).
- oligonucleotide is a linear polynucleotide sequence of up to about 100 nucleotide bases in length.
- reference to “at least 80% identity” refers to “at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% identity” to a specified reference sequence.
- reference to “at least 90% identity” refers to “at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% identity” to a specified reference sequence.
- an antibody or antigen binding fragment refers to a binding reaction which determines the presence of a target protein in the presence of a heterogeneous population of proteins and other biologics.
- an antibody binds preferentially to a particular target protein, peptide or polysaccharide (such as an antigen present on the surface of a T cell, for example canine PD-1) and does not bind in a significant amount to other proteins present in the sample or subject.
- Specific binding can be determined by standard methods. See Harlow & Lane, Antibodies, A Laboratory Manual, 2 nd ed., Cold Spring Harbor Publications, New York (2013), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.
- K D refers to the dissociation constant for a given interaction, such as a polypeptide ligand interaction or an antibody antigen interaction.
- K D refers to the concentration of the individual components of the bimolecular interaction divided by the concentration of the complex.
- An antibody such as a V H H monoclonal antibody, that specifically binds to an epitope on canine PD-1 is an antibody that binds substantially to canine PD-1 protein, including cells (such as T cells) or tissue expressing canine PD-1, substrate to which canine PD-1 is attached, or canine PD-1 protein in a biological specimen or isolated from a biological specimen. It is, of course, recognized that a certain degree of non-specific interaction may occur between an antibody and a non-target (such as a cell of the same tissue type that does not express canine PD-1). Typically, specific binding results in a much stronger association between the antibody and protein or cells bearing the antigen than between the antibody and protein or cells lacking the antigen.
- Specific binding typically results in greater than 2-fold, such as greater than 5-fold, greater than 10-fold, or greater than 100-fold increase in amount of bound antibody (per unit time) to a protein including the epitope or cell or tissue expressing the target epitope as compared to a protein or cell or tissue lacking this epitope.
- Specific binding to a protein under such conditions requires an antibody that is selected for its specificity for a particular protein.
- immunoassay formats are appropriate for selecting antibodies or other ligands specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein.
- Subject Living multi-cellular vertebrate organisms, a category that includes human and non-human mammals.
- a subject is a human.
- the subject has a cancer.
- a subject is selected that is in need of inhibiting of growth of a tumor or metastasis.
- the subject has be diagnosed with a tumor that expresses PD-L1, such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy, and is in need of treatment.
- PD-L1 such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck s
- T Cell A white blood cell critical to the immune response.
- T cells include, but are not limited to, CD4 + T cells and CD8 + T cells.
- a CD4 + T lymphocyte is an immune cell that expresses CD4 on its surface. These cells, also known as helper T cells, help orchestrate the immune response, including antibody responses as well as killer T cell responses.
- Th1 and Th2 cells are functional subsets of helper T cells. Th1 cells secrete a set of cytokines, including interferon-gamma, and whose principal function is to stimulate phagocyte-mediated defense against infections, especially related to intracellular microbes.
- Th2 cells secrete a set of cytokines, including interleukin (IL)-4 and IL-5, and whose principal functions are to stimulate IgE and eosinophil/mast cell-mediated immune reactions and to downregulate Th1 responses.
- IL interleukin
- Antigen specific CD8+ T cells become functionally tolerant (‘exhausted’) to a tumor antigen following the induction of the Programmed Death-1 polypeptide (PD-1). Accordingly, by reducing the expression or activity of PD-1, an immune response specific to an infectious agent or to tumor cells can be enhanced, see PCT Publication No. 2008/083174, incorporated herein by reference.
- Therapeutic agent Used in a generic sense, it includes treating agents, prophylactic agents, and replacement agents.
- a therapeutic agent is used to ameliorate a specific set of conditions in a subject with a disease or a disorder.
- Treating or preventing a disease Inhibiting the full development of a disease or condition, for example, in a subject who is at risk of or has a disease such as a tumor.
- Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition, such as a particular tumor type, after it has begun to develop.
- the term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment.
- the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
- a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.
- a transformed cell is a cell into which a nucleic acid molecule has been introduced by molecular biology techniques.
- transformed and the like encompasses all techniques by which a nucleic acid molecule might be introduced into such a cell, including transduction with viral vectors, transformation with plasmid vectors, and introduction of DNA by electroporation, lipofection, and particle gun acceleration.
- Vector An entity containing a nucleic acid molecule (such as a DNA or RNA molecule) bearing a promoter(s) that is operationally linked to the coding sequence of a protein of interest and can express the coding sequence.
- Non-limiting examples include a naked or packaged (lipid and/or protein) DNA, a naked or packaged RNA, a subcomponent of a virus or bacterium or other microorganism that may be replication-incompetent, or a virus or bacterium or other microorganism that may be replication-competent.
- a vector is sometimes referred to as a construct.
- Recombinant DNA vectors are vectors having recombinant DNA.
- a vector can include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication.
- a vector can also include one or more selectable marker genes and other genetic elements.
- Viral vectors are recombinant nucleic acid vectors having at least some nucleic acid sequences derived from one or more viruses.
- a viral vector comprises a nucleic acid molecule encoding a disclosed antibody or antigen binding fragment that specifically binds canine PD-1.
- PD-1 molecules are members of the immunoglobulin gene superfamily.
- the human PD-1 has an extracellular region containing immunoglobulin superfamily domain, a transmembrane domain, and an intracellular region including an immunoreceptor tyrosine-based inhibitory motif (ITIM) ((Ishida et al., EMBO J. 11:3887, 1992; Shinohara et al., Genomics 23:704, 1994; U.S. Pat. No. 5,698,520).
- ITIM immunoreceptor tyrosine-based inhibitory motif
- These features also define a larger family of molecules, called the immunoinhibitory receptors, which also includes gp49B, PIR-B, and the killer inhibitory receptors (KIRs) (Vivier and Daeron (1997) Immunol. Today 18:286).
- MHC major histocompatibility complex
- PD-1 is a 50-55 kDa type I transmembrane receptor that was originally identified in a T cell line undergoing activation-induced apoptosis. PD-1 is expressed on T cells, B cells, and macrophages.
- the ligands for PD-1 are the B7 family members PD-ligand 1 (PD-L1, also known as B7-H1) and PD-L2 (also known as B7-DC).
- PD-1 sequences are disclosed at GENBANK® Accession No. A13898677.1 and A13850882.1 (Canine mRNA). AAEX03014566.1 (Canine Genomic), and corresponding protein sequences, as available on Aug. 1, 2019.
- Human PD-1 sequences are disclosed at GEN BANK No. AC131097 (Human genomic) and AK313848 (Human cDNA), as available on Aug. 1, 2019.
- the disclosed VHH antibodies antigen binding fragments thereof specifically bind canine PD-1.
- PD-1 is expressed on activated T cells, B cells, and monocytes.
- Experimental data implicates the interactions of PD-1 with its ligands in downregulation of central and peripheral immune responses.
- proliferation in wild-type T cells but not in PD-1-deficient T cells is inhibited in the presence of PD-L1.
- PD-1-deficient mice exhibit an autoimmune phenotype.
- V H H Isolated V H H, monoclonal antibodies and antigen binding fragments thereof that specifically bind canine PD-1 are disclosed herein. These V H H, monoclonal antibodies and antigen binding fragments bind canine PD-1 and interfere with signaling by a ligand (such as PD-L1 or PD-L2) through PD-1. Thus, these V H H, monoclonal antibodies and antigen binding fragments thereof can be used to increase cytotoxic activity of exhausted T cells.
- a ligand such as PD-L1 or PD-L2
- compositions including the antibodies and antigen binding fragments and a pharmaceutically acceptable carrier.
- Nucleic acids encoding the antibodies or antigen binding fragments, expression vectors including these nucleic acids, and isolated host cells that express the nucleic acids are also provided.
- compositions comprising the V H H monoclonal antibodies and antigen binding fragments thereof (such as the V H H domain), that specifically bind canine PD-1 can be used for research, diagnostic and therapeutic purposes.
- the monoclonal antibodies can be used to increase cytotoxic T cell activity and can be used to treat a canine subject that has a tumor.
- the V H H monoclonal antibody, and antigen binding fragments thereof, that specifically bind canine PD-1 can be used to treat a tumor, such as, but not limited to an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- a tumor such as, but not limited to an osteosarcoma, a he
- V H H domain includes a complementarity determining region (CDR)1, a CDR2 and a CDR3, and wherein the V H H monoclonal antibodies or antigen binding fragments specifically binds a canine programmed death (PD)-1, such as dog PD-1, see, for Example, FIGS. 3 A- 3 B .
- PD canine programmed death
- the V H H monoclonal antibody or antigen binding fragment includes the CDR1, CDR2, or CDR3 of one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, and 113, and specifically binds canine PD-1.
- the CDR1 includes the amino acid sequence of SEQ ID NO: 2, the CDR2 includes the amino acid sequence of SEQ ID NO: 3, and/or the CDR3 includes amino the amino acid sequence of SEQ ID NO: 4; b) the CDR1 includes the amino acid sequence of SEQ ID NO: 6, the CDR2 includes the amino acid sequence of SEQ ID NO: 7, and/or the CDR3 includes amino the amino acid sequence of SEQ ID NO: 8; c) the CDR1 includes the amino acid sequence of SEQ ID NO: 10, the CDR2 includes the amino acid sequence of SEQ ID NO: 11, and/or the CDR3 includes amino the amino acid sequence of SEQ ID NO: 12; d) the CDR1 includes the amino acid sequence of SEQ ID NO: 14, the CDR2 includes the amino acid sequence of SEQ ID NO: 15, and/or the CDR3 includes amino the amino acid sequence of SEQ ID NO: 16; or e) the CDR1 includes the amino acid sequence of SEQ ID NO: 18, the CDR2
- the CDR1 includes the amino acid sequence of SEQ ID NO: 2, the CDR2 includes the amino acid sequence of SEQ ID NO: 3, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 4; b) the CDR1 includes the amino acid sequence of SEQ ID NO: 6, the CDR2 includes the amino acid sequence of SEQ ID NO: 7, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 8; c) the CDR1 includes the amino acid sequence of SEQ ID NO: 10, the CDR2 includes the amino acid sequence of SEQ ID NO: 11, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 12; d) the CDR1 includes the amino acid sequence of SEQ ID NO: 14, the CDR2 includes the amino acid sequence of SEQ ID NO: 15, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 16; or e) the CDR1 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes
- the V H H monoclonal antibody or antigen binding fragment includes a heavy chain variable domain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81 85, 89, 93, 97, 101, 105, 109, and 113, and specifically binds canine PD-1.
- the V H H monoclonal antibody or antigen binding fragment includes a heavy chain variable domain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NOs: 1, 5, 9, 13, or 17, and specifically binds canine PD-1.
- the CDR1 includes the amino acid sequence of SEQ ID NO: 2, the CDR2 includes the amino acid sequence of SEQ ID NO: 3, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 4; b) the CDR1 includes the amino acid sequence of SEQ ID NO: 6, the CDR2 includes the amino acid sequence of SEQ ID NO: 7, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 8; c) the CDR1 includes the amino acid sequence of SEQ ID NO: 10, the CDR2 includes the amino acid sequence of SEQ ID NO: 11, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 12; d) the CDR1 includes the amino acid sequence of SEQ ID NO: 14, the CDR2 includes the amino acid sequence of SEQ ID NO: 15, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 16; or e) the CDR1 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes
- the CDR1 includes the amino acid sequence of SEQ ID NO: 2, the CDR2 includes the amino acid sequence of SEQ ID NO: 3, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 4; b) the CDR1 includes the amino acid sequence of SEQ ID NO: 6, the CDR2 includes the amino acid sequence of SEQ ID NO: 7, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 8; c) the CDR1 includes the amino acid sequence of SEQ ID NO: 10, the CDR2 includes the amino acid sequence of SEQ ID NO: 11, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 12; d) the CDR1 includes the amino acid sequence of SEQ ID NO: 14, the CDR2 includes the amino acid sequence of SEQ ID NO: 15, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 16; or e) the CDR1 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes
- the CDR1 includes the amino acid sequence of SEQ ID NO: 2, the CDR2 includes the amino acid sequence of SEQ ID NO: 3, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 4; b) the CDR1 includes the amino acid sequence of SEQ ID NO: 6, the CDR2 includes the amino acid sequence of SEQ ID NO: 7, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 8; c) the CDR1 includes the amino acid sequence of SEQ ID NO: 10, the CDR2 includes the amino acid sequence of SEQ ID NO: 11, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 12; d) the CDR1 includes the amino acid sequence of SEQ ID NO: 14, the CDR2 includes the amino acid sequence of SEQ ID NO: 15, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 16; or e) the CDR1 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes the amino acid sequence of SEQ ID NO: 18, the CDR2 includes
- the V H H monoclonal antibody or antigen binding fragment includes at most 10, at most 9, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most two or at most one conservative amino acid substitutions in an amino acid sequence of one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81 85, 89, 93, 97, 101, 105, 109, and 113, and specifically binds canine PD-1.
- the heavy chain variable domain or antigen binding fragment includes at most 10, at most 9, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most two or at most one conservative amino acid substitutions in an amino acid sequence set forth as one of SEQ ID NOs: 1, 5, 9, 13, or 17.
- V H H monoclonal antibody and antigen binding fragments specifically bind canine PD-1.
- the CDR1 includes the amino acid sequence of SEQ ID NO: 2, the CDR2 includes the amino acid sequence of SEQ ID NO: 3, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 4; b) the CDR1 includes the amino acid sequence of SEQ ID NO: 6, the CDR2 includes the amino acid sequence of SEQ ID NO: 7, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 8; c) the CDR1 includes the amino acid sequence of SEQ ID NO: 10, the CDR2 includes the amino acid sequence of SEQ ID NO: 11, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 12; d) the CDR1 includes the amino acid sequence of SEQ ID NO: 14, the CDR2 includes the amino acid sequence of SEQ ID NO: 15, and the CDR3 includes amino the amino acid sequence of SEQ ID NO: 16; or e) the CDR1 includes the amino acid sequence of
- the V H H monoclonal antibody or antigen binding fragment includes the amino acid sequence of one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81 85, 89, 93, 97, 101, 105, 109, and 113.
- the V H H monoclonal antibody or antigen binding fragment includes the amino acid sequence of SEQ ID NOs: 1, 5, 9, 13, or 17.
- a V H H monoclonal antibody or antigen binding fragment can be a chimeric antibody or antigen binding fragment thereof.
- the antibody or antigen binding fragment can include any suitable framework region, such as (but not limited to) one or more human framework regions or canine regions. Human framework regions, and mutations that can be made in a human antibody framework region, are known in the art (see, for example, in U.S. Pat. No. 5,585,089, which is incorporated herein by reference).
- Chimeric antibodies can also include different mammalian region, such as a mouse framework region (See, for example, Jones et al., Nature 321:522, 1986; Riechmann et al., Nature 332:323, 1988; Verhoeyen et al., Science 239:1534, 1988; Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285, 1992; Sandhu, Crit. Rev. Biotech. 12:437, 1992; and Singer et al., J. Immunol.
- a mouse framework region See, for example, Jones et al., Nature 321:522, 1986; Riechmann et al., Nature 332:323, 1988; Verhoeyen et al., Science 239:1534, 1988; Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285, 1992; Sandhu, Crit. Rev. Biotech. 12
- FR1, FR2 and FR3 are canine.
- FR1 and FR3 are canine framework regions.
- FR2 can be caninised, excluding residues 42, 49 50 and 52.
- the FR2 is a llama framework region.
- the antibody can be of any isotype.
- the antibody can be, for example, a V H H IgG antibody.
- the class of an antibody that specifically binds canine PD-1 can be switched with another.
- a nucleic acid molecule encoding the V H H domain is isolated using methods well-known in the art, such that it does not include any nucleic acid sequences encoding the constant region.
- This nucleic acid molecule is then operatively linked to a nucleic acid sequence encoding a C H from a different class of immunoglobulin molecule, such as a canine constant domain.
- This can be achieved using a vector or nucleic acid molecule that includes a C H chain, as known in the art.
- an antibody that specifically binds canine PD-1 that was originally llama IgG may be class switched.
- the V H H monoclonal antibody or antigen binding fragment can specifically bind canine PD-1, such as dog PD-1, with an affinity (e.g., measured by K d ) of no more than 1.0 ⁇ 10 ⁇ 8 M, no more than 5.0 ⁇ 10 ⁇ 8 M, no more than 1.0 ⁇ 10 ⁇ 9 M, no more than 5.0 ⁇ 10 ⁇ 9 M, no more than 1.0 ⁇ 10 ⁇ 1 ° M, no more than 5.0 ⁇ 10 ⁇ 1 ° M, or no more than 1.0 ⁇ 10 ⁇ 11 M.
- K d can be measured, for example, by a radiolabeled antigen binding assay (RIA) performed with the V H H monoclonal antibody and canine PD-1 using known methods.
- RIA radiolabeled antigen binding assay
- solution binding affinity for antigen is measured by equilibrating Fab with a minimal concentration of 25 I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-V H H monoclonal antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)).
- MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 ⁇ g/ml of a capturing anti-PD-1 V H H monoclonal antibody in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23° C.).
- a non-adsorbent plate (Nunc #269620)
- 100 ⁇ M or 26 pM [ 125 I]-antigen are mixed with serial dilutions of a V H H of interest (e.g., consistent with assessment).
- V H H monoclonal antibody of interest is then incubated overnight; however, the incubation may continue for a longer period about 65 hours) to ensure that equilibriums is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed, and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 ⁇ l/well of scintillant (MICROSCINT-20TM; Packard) is added, and the plates are counted on a TOPCOUNTTM gamma counter (Packard) for ten minutes. Concentrations of each V H H monoclonal antibody that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.
- K d can be measured using surface plasmon resonance assays using a BIACORE® D-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25° C. with immobilized antigen CMS chips at ⁇ 10 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CMS, BIACORE®, Inc.) are activated with N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions.
- CMS carboxymethylated dextran biosensor chips
- EDC N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride
- NHS N-hydroxysuccinimide
- Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 ⁇ g/ml ( ⁇ 0.2 ⁇ M) before injection at a flow rate of 5 ⁇ minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25° C. at a flow rate of approximately 25 l/min.
- TWEEN-20TM polysorbate 20
- association rates (k on ) and dissociation rates (k off ) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams.
- the equilibrium dissociation constant (Kd) is calculated as the ratio k off /k on . See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999).
- the V H M monoclonal antibody or antigen binding fragment is included on a multispecific antibody, such as a bi-specific antibody.
- multispecific antibodies can be produced by known methods, such as crosslinking two or more antibodies, antigen binding fragments (such as an scFv) of the same type or of different types.
- Exemplary methods of making multispecific antibodies include those described in PCT Pub. No. WO2013/163427, which is incorporated by reference herein in its entirety.
- Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (such as m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (such as disuccinimidyl suberate).
- Such linkers are available from Pierce Chemical Company, Rockford, Ill.
- the V H H monoclonal antibody or antigen binding fragment is included on a bispecific antibody that that specifically binds to canine PD-1 and further specifically binds to a tumor antigen, such as Her-2, or any other tumor antigen.
- a tumor antigen such as Her-2, or any other tumor antigen.
- Exemplary tumor antigens are listed below:
- Tumor Tumor Antigens Acute myelogenous leukemia Wilms tumor 1 (WT1), preferentially expressed antigen of melanoma (PRAME), PR1, proteinase 3, elastase, cathepsin G Chronic myelogenous leukemia WT1, PRAME, PR1, proteinase 3, elastase, cathepsin G Myelodysplastic syndrome WT1, PRAME, PR1, proteinase 3, elastase, cathepsin G
- Acute lymphoblastic leukemia PRAME Chronic lymphocytic leukemia Survivin Non-Hodgkin's lymphoma Survivin Multiple myeloma New York esophageous 1 (NY-Eso1) Malignant melanoma MAGE, MART, Tyrosinase, PRAME, GP100
- WT1 herceptin Lung cancer
- PSA Prostate cancer Prostate-specific antigen
- Bispecific forms can also be produced that include two of the V H H monoclonal antibodies disclosed herein.
- One type of V H H antibody is produced by crosslinking two or more V H H to create bispecific antibodies called diabodies.
- Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (such as m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (such as disuccinimidyl suberate).
- Such linkers are available from Pierce Chemical Company, Rockford, Ill.
- the bispecific antibody includes a V H H that specifically binds a first epitope of canine PD-1, wherein the V H H is covalently linked to a first constant domain; and antigen binding fragment (such as an scFv or V H H) that specifically binds a second epitope of canine PD-1.
- V H H antigen binding fragment
- Any of the V H H disclosed herein can be included in the bispecific antibody.
- Exemplary bispecific antibodies are disclosed in the examples section. In one non-limiting example, the bispecific antibody is a diabody.
- the V H H or bispecific antibody can be derivatized or linked to another molecule (such as another peptide or protein).
- the V H H or bispecific antibody is derivatized such that the binding to canine PD-1 is not affected adversely by the derivatization or labeling.
- the V H H or bispecific antibody can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (for example, to form a bispecific antibody), a detection agent, a pharmaceutical agent, and/or a protein or peptide that can mediate association of the V H H or bispecific antibody with another molecule (such as a streptavidin core region or a polyhistidine tag).
- Polypeptides typically contain a variety of functional groups; such as carboxylic acid (COOH), free amine (—NH 2 ) or sulfhydryl (—SH) groups, which are available for reaction with a suitable functional group on a V H H, or a bispecific form thereof, to result in the binding of an effector molecule.
- the V H H, or bispecific form thereof can be derivatized to expose or attach additional reactive functional groups.
- the derivatization may involve attachment of any of a number of linker molecules such as those available from Pierce Chemical Company, Rockford, Ill.
- the linker can be any molecule used to join the V H H to another V H H, or to join the V H H or the bispecific antibody to the effector molecule.
- linker is capable of forming covalent bonds to both the V H H (or bispecific form thereof) and to the effector molecule.
- Suitable linkers are well known to those of skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers.
- the linkers may be joined to the constituent amino acids through their side groups (such as through a disulfide linkage to cysteine) or to the alpha carbon amino and carboxyl groups of the terminal amino acids.
- similar methods can be used to form a bispecific antibody, such as by attaching to V H H molecules together. Conjugates are further described below.
- Bispecific single chain antibodies can be encoded by a single nucleic acid molecule.
- Examples of bispecific single chain antibodies, as well as methods of constructing such antibodies are known in the art (see, e.g., U.S. Pat. Nos. 8,076,459, 8,017,748, 8,007,796, 7,919,089, 7,820,166, 7,635,472, 7,575,923, 7,435,549, 7,332,168, 7,323,440, 7,235,641, 7,229,760, 7,112,324, 6,723,538, incorporated by reference herein). Additional examples of bispecific single chain antibodies can be found in PCT application No. WO 99/54440; Mack, J.
- bispecific Fab-scFv (“bibody”) molecules are described, for example, in Schoonjans et al. (J. Immunol. 165:7050-57, 2000) and Willems et al. (J Chromatogr B Analyt Technol Biomed Life Sci. 786:161-76, 2003).
- a scFv molecule can be fused to one of the VL-CL (L) or VH-CH1 chains, e.g., to produce a bibody one scFv is fused to the C-term of a Fab chain.
- Antigen binding fragments are encompassed by the present disclosure, such as the V H H domain and specifically bind canine PD-1. These antibody fragments retain the ability to selectively bind with the antigen and are “antigen-binding” fragments.
- the constant domain is deleted or truncated.
- FR4 is truncated or deleted.
- one or more of the CDRs from a disclosed antibody is/are expressed on the surface of another protein, such as a scaffold protein.
- a scaffold protein The expression of domains of antibodies on the surface of a scaffolding protein are known in the art (see e.g. Liu et al., J. Virology 85(17): 8467-8476, 2011). Such expression creates a chimeric protein that retains the binding for canine PD-1.
- amino acid sequence variants of the V H H monoclonal antibodies and antigen binding fragments provided herein are contemplated.
- Amino acid sequence variants of a V H H monoclonal antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.
- V H H monoclonal antibody variants having one or more amino acid substitutions are provided.
- Sites of interest for substitutional mutagenesis include the CDRs and the framework regions.
- Amino acid substitutions may be introduced into a V H H monoclonal antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding to canine PD-1 and/or decreased immunogenicity.
- the variants typically retain amino acid residues necessary for correct folding and stabilizing between the regions is the V H H domain and retain the charge characteristics of the residues in order to preserve the low pI and low toxicity of the molecules.
- Amino acid substitutions can be made in the V H H domain to increase yield.
- Conservative amino acid substitution tables providing functionally similar amino acids are well known to one of ordinary skill in the art. The following six groups are examples of amino acids that are considered to be conservative substitutions for one another:
- the V H H domain includes up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence of one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81 85, 89, 93, 97, 101, 105, 109, and 113.
- amino acid substitutions such as conservative amino acid substitutions
- the antibody or antigen binding fragment can include up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) in the framework regions of the V H H domain, compared to a known framework region, or compared to the framework regions of the antibodies as disclosed herein, and maintain the specific binding activity for canine PD-1
- up to 10 such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9
- amino acid substitutions such as conservative amino acid substitutions
- substitutions, insertions, or deletions may occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the V H H monoclonal antibody to bind canine PD-1.
- conservative alterations e.g., conservative substitutions as provided herein
- binding affinity may be made in CDRs.
- each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.
- the V H H domain can be randomly mutated, such as within CDR3 region, in a process analogous to the in vivo somatic mutation process responsible for affinity maturation of antibodies during a natural immune response.
- affinity maturation can be accomplished by amplifying V H H domains using PCR primers complementary to the CDR3.
- the primers have been “spiked” with a random mixture of the four nucleotide bases at certain positions such that the resultant PCR products encode V H H domain into which random mutations have been introduced. These randomly mutated segments can be tested to determine the binding affinity for canine PD-1.
- a useful method for identification of residues or regions of a V H H monoclonal antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081-1085.
- a residue or group of target residues e.g., charged residues such as arg, asp, his, lys, and glu
- a neutral or negatively charged amino acid e.g., alanine or polyalanine
- Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions.
- a crystal structure of an antigen-V H H complex is used to identify contact points between the V H H monoclonal antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.
- a V H FI monoclonal antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available.
- the moieties suitable for derivatization of the V H H monoclonal antibody include but are not limited to water soluble polymers.
- Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.
- PEG polyethylene glycol
- copolymers of ethylene glycol/propylene glycol carboxymethylcellulose
- dextran polyvinyl alcohol
- Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.
- the polymer may be of any molecular weight and may be branched or unbranched.
- the number of polymers attached to the antibody may vary, and if more than one polymer is attached, it can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.
- the V H H monoclonal antibody or antigen binding fragment can be derivatized or linked to another molecule (such as another peptide or protein).
- the V H H monoclonal antibody or antigen binding fragment is derivatized such that the binding to canine PD-1 is not affected adversely by the derivatization or labeling.
- the V H H monoclonal antibody or antigen binding fragment can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (for example, a bi-specific antibody or a diabody), a detectable marker, an effector molecule, or a protein or peptide that can mediate association of the V H F′ monoclonal antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
- another antibody for example, a bi-specific antibody or a diabody
- a detectable marker for example, an effector molecule, or a protein or peptide that can mediate association of the V H F′ monoclonal antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
- antibodies that bind to the same epitope on canine PD-1 to which the disclosed antibodies provided herein bind.
- the antibody that binds to the same epitope on canine PD-1 and is a chimeric antibody.
- the V H H monoclonal antibodies, or antibody fragments disclosed herein can be derivatized or linked to another molecule (such as another peptide, protein, enzyme, chromogen or antibody).
- the derivatization is performed so that binding to canine PD-1 is not affected adversely by the derivatization or labeling.
- the antibody can be functionally linked, for example, by chemical coupling, genetic fusion, noncovalent association or otherwise to one or more other molecular entities, such as a detection agent and/or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
- a V H H monoclonal antibody, or antigen binding fragment thereof, that specifically binds canine PD-1 can be conjugated to a chemotherapeutic agent or toxin.
- These conjugates are of use for treating a T cell lymphoma that expresses PD-1 in a canine subject, such as, but not limited to, a dog.
- a T cell lymphoma that expresses PD-1 is angioimmunoblastic lymphoma.
- any T cell lymphoma that expresses PD-1 can be treated using these conjugates.
- a suitable method can be determined for attaching a given agent to an antibody or antigen binding fragment or other polypeptide(s).
- the antibody or antigen binding fragment can be conjugated with small molecular weight drugs such as Monomethyl Auristatin E (MMAE), Monomethyl Auristatin F (MMAF), maytansine, maytansine derivatives, including the derivative of maytansine known as DM1 (also known as mertansine), or other chemotherapeutic agents to make an antibody drug conjugate (ADC).
- MMAE Monomethyl Auristatin E
- MMAF Monomethyl Auristatin F
- maytansine maytansine derivatives, including the derivative of maytansine known as DM1 (also known as mertansine), or other chemotherapeutic agents to make an antibody drug conjugate (ADC).
- ADC antibody drug conjugate
- Toxins can be employed with a V H H monoclonal antibody, or antigen binding fragment thereof, that specifically binds canine PD-1.
- Exemplary toxins include Pseudomonas exotoxin (PE), ricin, abrin, diphtheria toxin and subunits thereof, ribotoxin, ribonuclease, saporin, and calicheamicin, as well as botulinum toxins A through F. These toxins are well known in the art and many are readily available from commercial sources (for example, Sigma Chemical Company, St. Louis, Mo.). Contemplated toxins also include variants of the toxins (see, for example, see, U.S. Pat. Nos. 5,079,163 and 4,689,401).
- Saporin is a toxin derived from Saponaria officinalis that disrupts protein synthesis by inactivating the 60S portion of the ribosomal complex (Stirpe et al., Bio/Technology, 10:405-412, 1992).
- the toxin has no mechanism for specific entry into cells, and therefore requires conjugation to an antibody or antigen binding fragment that recognizes a cell-surface protein that is internalized in order to be efficiently taken up by cells.
- Diphtheria toxin is isolated from Corynebacterium diphtheriae .
- diphtheria toxin for use in immunotoxins is mutated to reduce or to eliminate non-specific toxicity.
- a mutant known as CRM107 which has full enzymatic activity but markedly reduced non-specific toxicity, has been known since the 1970's (Laird and Groman, J. Virol. 19:220, 1976), and has been used in human clinical trials. See, U.S. Pat. Nos. 5,792,458 and 5,208,021.
- Ricin is the lectin RCA60 from Ricinus communis (Castor bean).
- Ricinus communis agglutinin occurs in two forms designated RCA 60 and RCA 120 according to their molecular weights of approximately 65 and 120 kD, respectively (Nicholson & Blaustein, J. Biochim. Biophys. Acta 266:543, 1972).
- the A chain is responsible for inactivating protein synthesis and killing cells.
- the B chain binds ricin to cell-surface galactose residues and facilitates transport of the A chain into the cytosol (Olsnes et al., Nature 249:627-631, 1974 and U.S. Pat. No. 3,060,165).
- Ribonucleases have also been conjugated to targeting molecules for use as immunotoxins (see Suzuki et al., Nat. Biotech. 17:265-70, 1999).
- Exemplary ribotoxins such as ⁇ -sarcin and restrictocin are discussed in, for example Rathore et al., Gene 190:31-5, 1997; and Goyal and Batra, Biochem. 345 Pt 2:247-54, 2000.
- Calicheamicins were first isolated from Micromonospora echinospora and are members of the enediyne antitumor antibiotic family that cause double strand breaks in DNA that lead to apoptosis (see, for example Lee et al., J. Antibiot. 42:1070-87, 1989). The drug is the toxic moiety of an immunotoxin in clinical trials (see, for example, Gillespie et al., Ann. Oncol. 11:735-41, 2000).
- Abrin includes toxic lectins from Abrus precatorius .
- the toxic principles, abrin a, b, c, and d have a molecular weight of from about 63 and 67 kD and are composed of two disulfide-linked polypeptide chains A and B.
- the A chain inhibits protein synthesis; the B chain (abrin-b) binds to D-galactose residues (see, Funatsu et al., Agr. Biol. Chem. 52:1095, 1988; and Olsnes, Methods Enzymol. 50:330-335, 1978).
- the toxin is Pseudomonas exotoxin (PE) (U.S. Pat. No. 5,602,095).
- PE includes full-length native (naturally occurring) PE or a PE that has been modified. Such modifications can include, but are not limited to, elimination of domain Ia, various amino acid deletions in domains Ib, II and III, single amino acid substitutions and the addition of one or more sequences at the carboxyl terminus (for example, see Siegall et al., J. Biol. Chem. 264:14256-14261, 1989).
- PE employed with the provided antibodies can include the native sequence, cytotoxic fragments of the native sequence, and conservatively modified variants of native PE and its cytotoxic fragments.
- Cytotoxic fragments of PE include those which are cytotoxic with or without subsequent proteolytic or other processing in the target cell. Cytotoxic fragments of PE include PE25, PE40, PE38, and PE35.
- Cytotoxic fragments of PE include PE25, PE40, PE38, and PE35.
- PCT Publication No. WO 99/51643 Pal et al., Proc. Natl. Acad. Sci. USA, 88:3358-3362, 1991; Kondo et al., J. Biol. Chem., 263:9470-9475, 1988; Pastan et al., Biochim. Biophys. Acta, 1333:C1-C6, 1997.
- PE-LR protease-resistant PE variants and PE variants with reduced immunogenicity
- PE-LR protease-resistant PE variants and PE variants with reduced immunogenicity
- PE-LR protease-resistant PE variants and PE variants with reduced immunogenicity
- PE-LR protease-resistant PE variants and PE variants with reduced immunogenicity
- PE-LR PE-LR
- PE-6X PE-8X
- PE-LR/6X PE-LR/6X
- PE-LR/8X see, for example, Weldon et al., Blood 113(16):3792-3800, 2009; Onda et al., Proc. Natl. Acad. Sci. USA, 105(32):11311-11316, 2008; and PCT Publication Nos. WO 2007/016150, WO 2009/032954 and WO 2011/032022, which are herein incorporated by reference).
- the PE variant can be PE25, see Weldon et al., Blood 2009; 113
- the PE is a variant that is resistant to lysosomal degradation, such as PE-LR (Weldon et al., Blood 113(16):3792-3800, 2009; PCT Publication No. WO 2009/032954).
- the PE is a variant designated PE-LR/6X (PCT Publication No. WO 2011/032022).
- the PE is a variant designated PE-LR/8M (PCT Publication No. WO 2011/032022).
- Effector molecules and detectable markers can be linked to a V H H monoclonal antibody, or antigen binding fragment thereof, that specifically binds canine PD-1, by any number of means known to those of skill in the art. Both covalent and non-covalent attachment means may be used.
- the procedure for attaching an effector molecule or detectable marker to an antibody or antigen binding fragment varies according to the chemical structure of the effector.
- Polypeptides typically contain a variety of functional groups; such as carboxylic acid (COOH), free amine (—NH 2 ) or sulfhydryl (—SH) groups, which are available for reaction with a suitable functional group on an antibody to result in the binding of the effector molecule or detectable marker.
- the antibody or antigen binding fragment is derivatized to expose or attach additional reactive functional groups.
- the derivatization may involve attachment of any of a number of known linker molecules such as those available from Pierce Chemical Company, Rockford, Ill.
- the linker can be any molecule used to join the antibody or antigen binding fragment to the effector molecule or detectable marker.
- the linker is capable of forming covalent bonds to both the antibody or antigen binding fragment and to the effector molecule or detectable marker.
- Suitable linkers are well known to those of skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers.
- the linkers may be joined to the constituent amino acids through their side groups (such as through a disulfide linkage to cysteine) or to the alpha carbon amino and carboxyl groups of the terminal amino acids.
- the linker can include a spacer element, which, when present, increases the size of the linker such that the distance between the effector molecule or the detectable marker and the antibody or antigen binding fragment is increased.
- spacers are known to the person of ordinary skill, and include those listed in U.S. Pat. Nos.
- a V H H monoclonal antibody, or antigen binding fragment thereof, that specifically binds canine PD-1 can be labeled with a detectable moiety.
- useful detection agents include fluorescent compounds, including fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin, lanthanide phosphors, ALEXA FLUOR® and the like.
- Bioluminescent markers are also of use, such as luciferase, green fluorescent protein (GFP), or yellow fluorescent protein.
- a V H H monoclonal antibody, or antigen binding fragment thereof can also be labeled with enzymes that are useful for detection, such as horseradish peroxidase, ⁇ -galactosidase, luciferase, alkaline phosphatase, glucose oxidase and the like.
- enzymes that are useful for detection, such as horseradish peroxidase, ⁇ -galactosidase, luciferase, alkaline phosphatase, glucose oxidase and the like.
- an antibody When an antibody is labeled with a detectable enzyme, it can be detected by adding additional reagents that the enzyme uses to produce a reaction product that can be discerned. For example, when the agent horseradish peroxidase is present the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is visually detectable.
- An antibody may also be labeled with biotin and detected through indirect measurement of avidin or streptavidin
- a V H H monoclonal antibody, or antigen binding fragment thereof may be labeled with a magnetic agent, such as gadolinium.
- Antibodies can also be labeled with lanthanides (such as europium and dysprosium), and manganese.
- Paramagnetic particles such as superparamagnetic iron oxide, are also of use as labels.
- An antibody may also be labeled with a predetermined polypeptide epitope recognized by a secondary reporter (such as leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags).
- labels are attached by spacer arms of various lengths to reduce potential steric hindrance.
- radiolabels include, but are not limited to, the following radioisotopes or radionucleotides: 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I.
- the radiolabel may be used for both diagnostic purposes.
- radiolabels may be detected using photographic film or scintillation counters
- fluorescent markers may be detected using a photodetector to detect emitted illumination
- Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label.
- radiolabels may be detected using photographic film or scintillation counters
- fluorescent markers may be detected using a photodetector to detect emitted illumination
- Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label.
- Nucleic acid molecules encoding the V H H monoclonal antibodies, antigen binding fragments, and conjugates are provided herein. These nucleic acid molecules can readily be produced by one of skill in the art, using the amino acid sequences provided herein (such as the CDR and V H H domain sequences), sequences available in the art (such as framework sequences), and the genetic code. One of skill in the art can readily use the genetic code to construct a variety of functionally equivalent nucleic acid molecules, such as nucleic acid molecules which differ in sequence but which encode the same V H H monoclonal antibody sequence, or encode a conjugate or fusion protein including a V H H domain.
- Nucleic acid molecules encoding the V H H monoclonal antibodies, antibody binding fragments, and conjugates that specifically bind canine PD-1 can be prepared by any suitable method including, for example, cloning of appropriate sequences or by direct chemical synthesis by methods such as the phosphotriester method of Narang et al., Meth. Enzymol. 68:90-99, 1979; the phosphodiester method of Brown et al., Meth. Enzymol. 68:109-151, 1979; the diethylphosphoramidite method of Beaucage et al., Tetra. Lett. 22:1859-1862, 1981; the solid phase phosphoramidite triester method described by Beaucage & Caruthers, Tetra. Letts.
- Exemplary nucleic acids can be prepared by cloning techniques. Examples of appropriate cloning and sequencing techniques, and instructions sufficient to direct persons of skill through many cloning exercises are known (see, e.g., Sambrook et al. (Molecular Cloning: A Laboratory Manual, 4 th ed, Cold Spring Harbor, N.Y., 2012) and Ausubel et al. (In Current Protocols in Molecular Biology, John Wiley & Sons, New York, through supplement 104, 2013). Product information from manufacturers of biological reagents and experimental equipment also provide useful information.
- Such manufacturers include the SIGMA Chemical Company (Saint Louis, Mo.), R&D Systems (Minneapolis, Minn.), Pharmacia Amersham (Piscataway, N.J.), CLONTECH Laboratories, Inc. (Palo Alto, Calif.), Chem Genes Corp., Aldrich Chemical Company (Milwaukee, Wis.), Glen Research, Inc., GIBCO BRL Life Technologies, Inc. (Gaithersburg, Md.), Fluka Chemica-Biochemika Analytika (Fluka Chemie AG, Buchs, Switzerland), Invitrogen (Carlsbad, Calif.), and Applied Biosystems (Foster City, Calif.), as well as many other commercial sources known to one of skill.
- Nucleic acid molecules can also be prepared by amplification methods.
- Amplification methods include polymerase chain reaction (PCR), the ligase chain reaction (LCR), the transcription-based amplification system (TAS), the self-sustained sequence replication system (3SR).
- PCR polymerase chain reaction
- LCR ligase chain reaction
- TAS transcription-based amplification system
- 3SR self-sustained sequence replication system
- the nucleic acid molecule encoding the V H H monoclonal antibody, or antigen binding fragment thereof can be included in a vector (such as a lentiviral vector) for expression in a host cell.
- the host cell can be prokaryotic or eukaryotic.
- the nucleic acid molecules can be expressed in a recombinantly engineered cell such as bacteria, plant, yeast, insect and mammalian cells. Methods of expressing and purifying antibodies and antigen binding fragments are known and further described herein (see, e.g., Al-Rubeai (ed), Antibody Expression and Production , Springer Press, 2011). Those of skill in the art are knowledgeable in the numerous expression systems available for expression of proteins including E.
- One or more DNA sequences encoding the V H H monoclonal antibody, antigen binding fragment thereof, or conjugate thereof, can be expressed in vitro by DNA transfer into a suitable host cell.
- the term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. Methods of stable transfer, meaning that the foreign DNA is continuously maintained in the host, are known in the art.
- Polynucleotide sequences encoding a V H H monoclonal antibody, antigen binding fragment thereof, or conjugate thereof can be operatively linked to expression control sequences.
- An expression control sequence operatively linked to a coding sequence is ligated such that expression of the coding sequence is achieved under conditions compatible with the expression control sequences.
- the expression control sequences include, but are not limited to appropriate promoters, enhancers, transcription terminators, a start codon (i.e., ATG) in front of a protein-encoding gene, splicing signal for introns, maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons.
- expression cassettes which contain, at the minimum, a strong promoter to direct transcription, a ribosome binding site for translational initiation (internal ribosomal binding sequences), and a transcription/translation terminator.
- a strong promoter to direct transcription e. coli
- a ribosome binding site for translational initiation e. coli
- a transcription/translation terminator e. coli
- control sequences can include a promoter and/or an enhancer derived from, for example, an immunoglobulin gene, HTLV, SV40 or cytomegalovirus, and a polyadenylation sequence, and can further include splice donor and/or acceptor sequences (for example, CMV and/or HTLV splice acceptor and donor sequences).
- the cassettes can be transferred into the chosen host cell by well-known methods such as transformation or electroporation for E. coli and calcium phosphate treatment, electroporation or lipofection for mammalian cells. Cells transformed by the cassettes can be selected by resistance to antibiotics conferred by genes contained in the cassettes, such as the amp, gpt, neo and hyg genes.
- Modifications can be made to a nucleic acid encoding a polypeptide described herein without diminishing its biological activity. Some modifications can be made to facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications are well known to those of skill in the art and include, for example, termination codons, a methionine added at the amino terminus to provide an initiation, site, additional amino acids placed on either terminus to create conveniently located restriction sites, or additional amino acids (such as poly His) to aid in purification steps.
- the nucleic acid molecule encoding the antibody, or antigen binding fragment or conjugate thereof can be inserted into an expression vector including, but not limited to a plasmid, virus or other vehicle that can be manipulated to allow insertion or incorporation of sequences and can be expressed in either prokaryotes or eukaryotes.
- Hosts can include microbial, yeast, insect and mammalian organisms. Methods of expressing DNA sequences having eukaryotic or viral sequences in prokaryotes are well known in the art. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art.
- Eukaryotic cells can also be co-transformed with polynucleotide sequences encoding the antibody, labeled antibody, or antigen binding fragment thereof, and a second foreign DNA molecule encoding a selectable phenotype, such as the herpes simplex thymidine kinase gene.
- Another method is to use a eukaryotic viral vector, such as simian virus 40 (SV40) or bovine papilloma virus, to transiently infect or transform eukaryotic cells and express the protein (see for example, Viral Expression Vectors, Springer press, Muzyczka ed., 2011).
- a eukaryotic viral vector such as simian virus 40 (SV40) or bovine papilloma virus
- SV40 simian virus 40
- bovine papilloma virus bovine papilloma virus
- the population of cells can be a heterogeneous population including the host cell including any of the recombinant expression vectors described, in addition to at least one other cell, e.g., a host cell (e.g., a T cell), which does not comprise any of the recombinant expression vectors, or a cell other than a T cell, e.g., a B cell, a macrophage, a neutrophil, an erythrocyte, a hepatocyte, an endothelial cell, an epithelial cell, a muscle cell, a brain cell, etc.
- a host cell e.g., a T cell
- a cell other than a T cell e.g., a B cell, a macrophage, a neutrophil, an erythrocyte, a hepatocyte, an endothelial cell, an epithelial cell, a muscle cell, a brain cell, etc.
- the population of cells can be a substantially homogeneous population, in which the population includes mainly host cells (e.g., consisting essentially of) including the recombinant expression vector.
- the population also can be a clonal population of cells, in which all cells of the population are clones of a single host cell including a recombinant expression vector, such that all cells of the population comprise the recombinant expression vector.
- the population of cells is a clonal population including host cells including a recombinant expression vector as described herein
- V H H monoclonal antibodies, antigen binding fragments, and conjugates, and/or refolding to an appropriate active form, from mammalian cells, and bacteria such as E. coli have been described and are well-known and are applicable to the antibodies disclosed herein. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, 2 nd , Cold Spring Harbor Laboratory, New York, 2013, Simpson ed., Basic methods in Protein Purification and Analysis: A laboratory Manual, Cold Harbor Press, 2008, and Ward et al., Nature 341:544, 1989. Often, functional heterologous proteins from E. coli or other bacteria are isolated from inclusion bodies and require solubilization using strong denaturants, and subsequent refolding.
- a reducing agent must be present.
- An exemplary buffer with a reducing agent is: 0.1 M Tris pH 8, 6 M guanidine, 2 mM EDTA, 0.3 M DTE (dithioerythritol).
- V H H monoclonal antibodies, antigen binding fragments, and conjugates of the present disclosure can also be constructed in whole or in part using standard peptide synthesis well known in the art.
- Solid phase synthesis of polypeptides can be accomplished by attaching the C-terminal amino acid of the sequence to an insoluble support followed by sequential addition of the remaining amino acids in the sequence. Techniques for solid phase synthesis are described by Barany & Merrifield, The Peptides: Analysis, Synthesis, Biology. Vol. 2 : Special Methods in Peptide Synthesis, Part A . pp. 3-284; Merrifield et al., J. Am. Chem. Soc.
- Proteins of greater length may be synthesized by condensation of the amino and carboxyl termini of shorter fragments. Methods of forming peptide bonds by activation of a carboxyl terminal end (such as by the use of the coupling reagent N, N′-dicylohexylcarbodimide) are well known in the art.
- V H H monoclonal antibodies, antigen binding fragments, and conjugates can be purified according to standard procedures in the art, including ammonium sulfate precipitation, affinity columns, column chromatography, and the like (see, generally, Simpson ed., Basic methods in Protein Purification and Analysis: A laboratory Manual, Cold Harbor Press, 2008).
- the antibodies, antigen binding fragment, and conjugates need not be 100% pure.
- the polypeptides should be substantially free of endotoxin.
- Methods are provided for detecting the presence of a canine cell that expresses PD-1 in a canine subject, such as a T cell, for example an exhausted T cell.
- a canine subject such as a T cell, for example an exhausted T cell.
- the subject can be any canine subject, such as, but not limited to, a dog.
- the methods include contacting a sample including cells from a subject with one or more of the disclosed V H H monoclonal antibodies, antigen binding fragments, or conjugates to form an immune complex. The presence (or absence) of the immune complex is then detected. The presence of the immune complex indicates the presence of a cell that expresses canine PD-1 in the subject.
- the detection methods can involve in vivo detection or in vitro detection of the immune complex.
- detection of a cell that expresses canine PD-1 includes detecting cell-surface expression of canine PD-1 on a T cell. In several embodiments of the provided methods, detecting a T cell that expresses canine PD-1 in a subject detects the presence of exhausted T cells.
- the sample is obtained from a subject with a tumor, such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- a tumor such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adeno
- a variety of formats are of use for detecting a cell that expresses canine PD-1, for example, a T cell that expresses canine PD-1.
- a subject is selected who has, is suspected of having, or is at risk of developing, a tumor, for example, an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hemat
- a sample is obtained from a subject, and the presence of a T cell that expresses canine PD-1 is assessed in vitro.
- such methods include contacting a T cell in a biological sample from the subject with one or more of the V H H monoclonal antibodies, antigen binding fragments or conjugates provided herein that specifically bind canine PD-1 to form an immune complex. The presence (or absence) of the immune complex is then detected. The presence of the immune complex on the cell from the subject indicates the presence of a T cell that expresses PD-1 in the canine subject.
- an increase in the presence of the immune complex in the sample as compared to formation of the immune complex in a control sample indicates the presence of one or more T cells that express PD-1, such as exhausted T cells, in the canine subject.
- a control can be utilized.
- the control can be a standard value, or a sample from a canine that does not have the tumor.
- the biological sample can be any sample, including, but not limited to, blood, blood products, tissue from biopsies, such as from tumors, autopsies and pathology specimens. Biological samples also include sections of tissues, for example, frozen sections taken for histological purposes.
- the V H H monoclonal antibody or antigen binding fragment thereof is conjugated to a detectable marker.
- the methods further include contacting a second antibody that specifically binds the Vial monoclonal antibody, antigen binding fragment thereof, or a conjugate including these molecules, for a sufficient amount of time to form an immune complex and detecting this immune complex.
- An increase in the presence of this immune complex in a biological sample from a selected subject (as described above) compared to the presence of the immune complex in a control sample or other standard detects the presence of a T cell that expresses canine PD-1 in the biological sample.
- the second antibody is conjugated to a detectable marker.
- Suitable detectable markers for the antibody or secondary antibody are described and known to the skilled artisan.
- various enzymes, prosthetic groups, fluorescent materials, luminescent materials, magnetic agents and radioactive materials include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase.
- suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin.
- suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin.
- a non-limiting exemplary luminescent material is luminol; a non-limiting exemplary a magnetic agent is gadolinium, and non-limiting exemplary radioactive labels include 125 I, 131 I, 35 S or 3 H.
- the antibodies that specifically bind canine PD-1 and conjugates thereof can be used in immunohistochemical assays. These assays are well known to one of skill in the art (see Harlow & Lane, Antibodies, A Laboratory Manual, 2 nd ed., Cold Spring Harbor Publications, New York (2013), for a description of immunoassay formats
- immune complex detection include radiolocalization, radioimaging, magnetic resonance imaging (such as using a biotinylated antibody and avidin-iron oxide), positron emission tomography (such as using an 111 indium-labeled monoclonal antibody) or fluorescence imaging (such as using luciferase or green fluorescent protein labeled antibodies). See Paty et al., Transplantation., 77:1133-1137, 2004, herein incorporated by reference.
- contrast agent detection can be greatly impacted by magnetic resonance scanner field strength. Increased field strengths provide improvements by orders of magnitude in the ability to detect contrast agents (Hu et al., Ann. Rev. Biomed. Eng., 6:157-184, 2004; Wedeking et al., Magn. Reson. Imaging., 17:569-575, 1999).
- the limit of detection of gadolinium at 2 tesla (T) is ⁇ 30 ⁇ M. At 4T the limit of detection is reduced to ⁇ 1 ⁇ M. With newly available 7 to 12T scanners one would expect to detect low (10-100) nM concentrations of this contrast agent. Similar sensitivity can also be identified using contrast agents such as iron oxide.
- Methods are disclosed for increasing cytotoxic activity of T cells in a canine subject, such as, but not limited to, a dog.
- administration of a therapeutically effective amount of the V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate (or a nucleic acid encoding these molecules) increases cytotoxic T cell activity in the subject.
- the subject can have a tumor, such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- Methods are also disclosed for treating these tumors in a canine subject, such as a dog.
- a therapeutically effective amount of a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate can be administered to a subject to treat a tumor, such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- a tumor such as an osteosarcoma, a hemangios
- the V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate disclosed herein can be administered to a subject to slow or inhibit the growth or metastasis of a tumor, reduce tumor volume and/or reduce metastasis.
- a therapeutically effective amount of the V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate (or a nucleic acid encoding these molecules) is administered to a subject in an amount and under conditions sufficient to form an immune complex with canine PD-1, thereby increasing T cell activity, such as cytotoxic T cell activity.
- suitable subjects include those diagnosed with or suspecting of having an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- the therapeutically effective amount will depend upon the severity of the disease and the general state of the canine subject's health.
- a therapeutically effective amount is that which provides either subjective relief of a symptom(s) or an objectively identifiable improvement as noted by the clinician or other qualified observer.
- a therapeutically effective amount is the amount necessary to inhibit tumor growth, inhibit metastasis, reduce tumor volume, and/or the amount that is effective at reducing a sign or a symptom of the tumor.
- a therapeutically effective amount is sufficient to increase cytotoxicity in a canine subject.
- the therapeutically effective amount of the agents administered can vary depending upon the desired effects and the canine subject to be treated. In some examples, therapeutic amounts are amounts which eliminate or reduce the tumor burden, or which prevent or reduce the proliferation of metastatic cells, or reduce a symptom of the tumor.
- Canine subjects can be screened prior to initiating the disclosed therapies, for example to determine whether the canine has a tumor.
- these a canine subject can be selected for treatment that has a tumor, such as an osteosarcoma, a hemangiosarcoma, a soft tissue, a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocytic sarcoma, a mast cell tumor, or a hematologic malignancy.
- a tumor such as an osteosarcoma, a
- any method of administration can be used for the a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate, nucleic acid molecules and/or pharmaceutical compositions including these agents, including local and systemic administration.
- intratumoral, oral, intravascular such as intratumoral, intravenous, intramuscular, intraperitoneal, intranasal, intradermal, intrathecal and subcutaneous administration can be used.
- intravenous administration is utilized.
- the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (for example the subject, the disease, and the disease state involved).
- one or more routes of administration may be used; for example, a chemotherapeutic agent may be administered orally and a V H H monoclonal antibody, antigen binding fragment, conjugate, bispecific antibody, or composition including one or more of these agents may be administered intravenously. Methods of administration include injection.
- the a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate is provided in a nontoxic pharmaceutically acceptable carrier, such as water, saline, Ringer's solution, dextrose solution, 5% human serum albumin, fixed oils, ethyl oleate, or liposomes.
- local administration of the disclosed a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate can be used, for instance by application to a region of tissue from which a tumor has been removed, or a region suspected of being prone to tumor development.
- sustained intra-tumoral (or near-tumoral) release of the pharmaceutical preparation that includes a therapeutically effective amount of the antibody or antigen binding fragment (or conjugate thereof) may be beneficial.
- a slow release formulation or a delivery device is utilized.
- compositions that include a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate (or a nucleic acid encoding these molecules) can be formulated in unit dosage form suitable for individual administration of precise dosages.
- the compositions may be administered in a single dose or in a multiple dose schedule.
- a multiple dose schedule is one in which a primary course of treatment may be with more than one separate dose, for instance 1-10 doses, followed by other doses given at subsequent time intervals as needed to maintain or reinforce the action of the compositions.
- Treatment can involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years.
- the dosage regime will also, at least in part, be determined based on the particular needs of the canine subject to be treated and will be dependent upon the judgment of the administering practitioner, such as a veterinarian.
- Typical dosages of the a V H H monoclonal antibody, antigen binding fragment, or conjugate can range from about 0.01 to about 30 mg/kg, such as from about 0.1 to about 10 mg/kg.
- the dosage is at least about 0.1 mg/kg, at least about 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4 mg/kg, at least about 0.5 mg/kg, at least about 1 mg/kg, at least about 4 mg/kg, at least about 3 mg/kg, at least about 5 mg/kg, at least about 6 mg/kg, at least about 7 mg/kg, at least about 8 mg/kg is at least about 9 mg/kg, at least about 10 mg/kg, at least about 11 mg/kg, at least about 12 mg/kg, at least about 13 mg/kg, at least about 14 mg/kg, at least about 15 mg/kg, at least about 16 mg/kg, at least about 17 mg/kg, at least about 18 mg/kg, at least about 19 mg/kg, at least about 20 mg/kg,
- the subject is administered a therapeutic composition that includes one or more of the a Vial monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate on a multiple daily dosing schedule, such as at least two consecutive days, 10 consecutive days, and so forth, for example for a period of weeks, months, or years.
- the subject is administered the conjugates, antibodies, compositions or additional agents for a period of at least 30 days, such as at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 24 months, or at least 36 months.
- a disclosed therapeutic agent is administered may be administered intravenously, subcutaneously or by another mode daily or multiple times per week for a period of time, followed by a period of no treatment, then the cycle is repeated.
- the initial period of treatment e.g., administration of the therapeutic agent daily or multiple times per week
- the period of no treatment lasts for 3 days, 1 week, 2 weeks, 3 weeks or 4 weeks.
- the dosing regimen of the therapeutic agent is daily for 3 days followed by 3 days off; or daily or multiple times per week for 1 week followed by 3 days or 1 week off; or daily or multiple times per week for 2 weeks followed by 1 or 2 weeks off; or daily or multiple times per week for 3 weeks followed by 1, 2 or 3 weeks off; or daily or multiple times per week for 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks followed by 1, 2, 3 or 4 weeks off.
- Administration of the a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate, or compositions can be accompanied by administration of other anti-cancer or anti-angiogenesis agents or therapeutic treatments (such as surgical resection of a tumor or radiation therapy).
- the subject prior to, during, or following administration of a therapeutic amount of the a V H H monoclonal antibody, antigen binding fragment, bispecific antibody, or conjugate the subject can receive one or more additional therapies.
- the subject receives one or more treatments to remove or reduce the tumor.
- the additional agent may include, but is not limited to, a chemotherapeutic agent, an anti-angiogenic agent, or a combination thereof.
- at least part of the tumor is surgically or otherwise excised or reduced in size or volume prior to administering the therapeutically effective amount of the antibody or antigen binding fragment or conjugate.
- additional therapeutic agents include microtubule binding agents, DNA intercalators or cross-linkers, DNA synthesis inhibitors, DNA and RNA transcription inhibitors, antibodies, enzymes, enzyme inhibitors, gene regulators, and angiogenesis inhibitors.
- these agents (which are administered at a therapeutically effective amount) and treatments can be used alone or in combination.
- any suitable anti-cancer or anti-angiogenic agent can be administered in combination with the V H H monoclonal antibody, antigen binding fragment, or conjugate. Methods and therapeutic dosages of such agents are known to those skilled in the art, and can be determined by a skilled clinician.
- the chemotherapeutic agent includes 5-FU or IRT or both.
- DNA and RNA transcription regulators including, without limitation, actinomycin D, daunorubicin, doxorubicin and derivatives and analogs thereof also are suitable for use in combination with the disclosed therapies.
- DNA intercalators and cross-linking agents that can be administered to a subject include, without limitation, cisplatin, carboplatin, oxaliplatin, mitomycins, such as mitomycin C, bleomycin, chlorambucil, cyclophosphamide and derivatives and analogs thereof.
- DNA synthesis inhibitors suitable for use as therapeutic agents include, without limitation, methotrexate, 5-fluoro-5′-deoxyuridine, 5-FU and analogs thereof.
- Suitable enzyme inhibitors include, without limitation, camptothecin, etoposide, formestane, trichostatin and derivatives and analogs thereof.
- Suitable compounds that affect gene regulation include agents that result in increased or decreased expression of one or more genes, such as raloxifene, 5-azacytidine, 5-aza-2′-deoxycytidine, tamoxifen, 4-hydroxytamoxifen, mifepristone and derivatives and analogs thereof.
- Examples of the commonly used chemotherapy drugs include Adriamycin, Alkeran, Ara-C, BiCNU, Busulfan, CCNU, Carboplatinum, Cisplatinum, Cytoxan, Daunorubicin, DTIC, 5-FU, Fludarabine, Hydrea, Idarubicin, Ifosfamide, Methotrexate, Mithramycin, Mitomycin, Mitoxantrone, Nitrogen Mustard, Taxol (or other taxanes, such as docetaxel), Velban, Vincristine, VP-16, while some more newer drugs include Gemcitabine (Gemzar), Herceptin, IRT (Camptosar, CPT-11), Leustatin, Navelbine, Rituxan STI-571, Taxotere, Topotecan (Hycamtin), Xeloda (Capecitabine), Zevelin and calcitriol.
- Non-limiting examples of immunomodulators that can be used include AS-101 (Wyeth-Ayerst Labs.), bropirimine (Upjohn), gamma interferon (Genentech), GM-CSF (granulocyte macrophage colony stimulating factor; Genetics Institute), IL-2 (Cetus or Hoffman-LaRoche), human immune globulin (Cutter Biological), IMREG (from Imreg of New Jersey, La.), SK&F 106528, and TNF (tumor necrosis factor; Genentech).
- Non-limiting examples of anti-angiogenic agents include molecules, such as proteins, enzymes, polysaccharides, oligonucleotides, DNA, RNA, and recombinant vectors, and small molecules that function to reduce or even inhibit blood vessel growth.
- suitable angiogenesis inhibitors include, without limitation, angiostatin K1-3, staurosporine, genistein, fumagillin, medroxyprogesterone, suramin, interferon-alpha, metalloproteinase inhibitors, platelet factor 4, somatostatin, thromobospondin, endostatin, thalidomide, and derivatives and analogs thereof.
- the additional agent is a monoclonal antibody, for example, 3F8, Abagovomab, Adecatumumab, Afutuzumab, Alacizumab, Alemtuzumab, Altumomab pentetate, Anatumomab mafenatox, Apolizumab, Arcitumomab, Bavituximab, Bectumomab, Belimumab, Besilesomab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, Capromab pendetide, Catumaxomab, CC49, Cetuximab, Citatuzumab, Citatuzumab communicatingox, Cixutumumab, Clivatuzumab tetraxetan, Conatumumab
- Another common treatment for some types of tumors is surgical treatment, for example surgical resection of the cancer or a portion of it.
- surgical treatment for example surgical resection of the cancer or a portion of it.
- radiotherapy for example administration of radioactive material or energy (such as external beam therapy) to the tumor site to help eradicate the tumor or shrink it prior to surgical resection.
- the disclosed compositions can be used in conjunction with surgical resection or with radiation therapy.
- anti-tumor agents for example anti-tumor agents, that may or may not fall under one or more of the classifications above, also are suitable for administration in combination with the disclosed therapies.
- agents include adriamycin, apigenin, rapamycin, zebularine, cimetidine, and derivatives and analogs thereof.
- Preparation and dosing schedules for the additional agent may be used according to manufacturer's instructions or as determined empirically by the skilled practitioner. Preparation and dosing schedules for such chemotherapy are also described in Chemotherapy Service, (1992) Ed., M. C. Perry, Williams & Wilkins, Baltimore, Md.
- the combination therapy may provide synergy and prove synergistic, that is, the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
- a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
- a synergistic effect may be attained when the compounds are administered or delivered sequentially, for example by different injections in separate syringes.
- an effective dosage of each active ingredient is administered sequentially, i.e. serially
- combination therapy effective dosages of two or more active ingredients are administered together.
- compositions include a disclosed V H H monoclonal antibody, antigen binding fragment, bispecific antibody, conjugate, nucleic acid molecule, or vector in a carrier (such as a pharmaceutically acceptable carrier).
- the compositions can be prepared in unit dosage forms for administration to a subject. The amount and timing of administration are at the discretion of the treating clinician to achieve the desired outcome.
- the compositions can be formulated for systemic (such as intravenous) or local (such as intra-tumor) administration.
- an effective amount of the disclosed V H H monoclonal antibody, antigen binding fragment, conjugate, or nucleic acid molecule is/are formulated for parenteral administration, such as intravenous administration.
- Compositions including a disclosed Vial monoclonal antibody, antigen binding fragment, conjugate, bispecific antibody, or nucleic acid molecules as disclosed herein are of use, for example, for the treatment and/or detection of a tumor.
- compositions for administration can include a solution of the disclosed V H H monoclonal antibody, antigen binding fragments, conjugate, or nucleic acid molecule (or expression vector) in a pharmaceutically acceptable carrier, such as an aqueous carrier.
- a pharmaceutically acceptable carrier such as an aqueous carrier.
- aqueous carriers can be used, for example, buffered saline and the like. These solutions are sterile and generally free of undesirable matter.
- These compositions may be sterilized by conventional, well known sterilization techniques.
- the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
- concentration of the active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject's needs. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.
- a typical composition including a V H H monoclonal antibody, antigen binding fragment thereof, bispecific antibody, or conjugate, for intravenous administration includes about 0.01 to about 30 mg/kg per canine subject per day.
- Actual methods for preparing administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, Pa. (1995).
- the composition can be a liquid formulation including one or more V H H monoclonal antibodies, antigen binding fragment thereof, or conjugate in a concentration range from about 0.1 mg/ml to about 20 mg/ml, or from about 0.5 mg/ml to about 20 mg/ml, or from about 1 mg/ml to about 20 mg/ml, or from about 0.1 mg/ml to about 10 mg/ml, or from about 0.5 mg/ml to about 10 mg/ml, or from about 1 mg/ml to about 10 mg/ml.
- V H H monoclonal antibodies, antigen binding fragments, bispecific antibodies, or conjugates may be provided in lyophilized form and rehydrated with sterile water before administration, although they are also provided in sterile solutions of known concentration.
- the V H H monoclonal antibody or antigen binding fragment or conjugate solution is then added to an infusion bag containing 0.9% sodium chloride, USP, and in some cases administered at a dosage of from 0.5 to 15 mg/kg of body weight.
- V H H monoclonal antibodies, antigen binding fragments, bispecific antibodies, and conjugates can be administered by slow infusion, rather than in an intravenous push or bolus.
- a higher loading dose is administered, with subsequent, maintenance doses being administered at a lower level.
- an initial loading dose of 4 mg/kg antibody or antigen binding fragment (or the corresponding dose of a conjugate including the antibody or antigen binding fragment) may be infused over a period of some 90 minutes, followed by weekly maintenance doses for 4-8 weeks of 2 mg/kg infused over a 30 minute period if the previous dose was well tolerated.
- Controlled release parenteral formulations can be made as implants, oily injections, or as particulate systems.
- Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles.
- Microcapsules contain the therapeutic protein, such as a cytotoxin or a drug, as a central core. In microspheres the therapeutic is dispersed throughout the particle.
- Particles, microspheres, and microcapsules smaller than about 1 ⁇ m are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively.
- Capillaries have a diameter of approximately 5 ⁇ m so that only nanoparticles are administered intravenously.
- Microparticles are typically around 100 ⁇ m in diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, J., Colloidal Drug Delivery Systems , J. Kreuter, ed., Marcel Dekker, Inc., New York, N.Y., pp. 219-342 (1994); and Tice & Tabibi, Treatise on Controlled Drug Delivery , A. Kydonieus, ed., Marcel Dekker, Inc. New York, N.Y., pp. 315-339, (1992).
- Polymers can be used for ion-controlled release of the antibody or antigen binding fragment or conjugate compositions disclosed herein.
- Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, Accounts Chem. Res. 26:537-542, 1993).
- the block copolymer, polaxamer 407 exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has been shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin-2 and urease (Johnston et al., Pharm. Res. 9:425-434, 1992; and Pec et al., J. Parent. Sci. Tech.
- hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm. 112:215-224, 1994).
- liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems , Technomic Publishing Co., Inc., Lancaster, Pa. (1993)). Numerous additional systems for controlled delivery of therapeutic proteins are known (see U.S. Pat. Nos.
- a canine subject is administered the DNA encoding the V H H monoclonal antibody, antigen binding fragments thereof, bi specific antibody, or conjugate to provide in vivo antibody production, for example using the cellular machinery of the subject.
- Immunization by nucleic acid constructs is well known in the art and taught, for example, in U.S. Pat. Nos. 5,643,578, and 5,593,972 and 5,817,637.
- U.S. Pat. No. 5,880,103 describes several methods of delivery of nucleic acids encoding to an organism. The methods include liposomal delivery of the nucleic acids. Such methods can be applied to the production of a V H H monoclonal antibody, or antibody binding fragments thereof, by one of ordinary skill in the art.
- nucleic acids are direct administration with plasmid DNA, such as with a mammalian expression plasmid.
- plasmid DNA such as with a mammalian expression plasmid.
- the nucleotide sequence encoding the disclosed antibody, or antibody binding fragments thereof, can be placed under the control of a promoter to increase expression.
- a disclosed antibody, or antibody binding fragments thereof, or bispecific antibody can also be expressed by attenuated viral hosts or vectors or bacterial vectors.
- Recombinant vaccinia virus, adeno-associated virus (AAV), herpes virus, retrovirus, cytomegalovirus or other viral vectors can be used to express the antibody.
- vaccinia vectors and methods useful protocols are described in U.S. Pat. No. 4,722,848.
- BCG Bacillus Calmette Guerin provides another vector for expression of the disclosed antibodies (see Stover, Nature 351:456-460, 1991).
- a nucleic acid encoding a disclosed V H H monoclonal antibody, or antibody binding fragment thereof, or bispecific antibody is introduced directly into cells.
- the nucleic acid can be loaded onto gold microspheres by standard methods and introduced into the skin by a device such as Bio-Rad's HELIOSTM Gene Gun.
- the nucleic acids can be “naked,” consisting of plasmids under control of a strong promoter.
- the DNA is injected into muscle, although it can also be injected directly into other sites.
- Dosages for injection are usually around 0.5 ⁇ g/kg to about 50 mg/kg, and typically are about 0.005 mg/kg to about 5 mg/kg (see, e.g., U.S. Pat. No. 5,589,466).
- Kits are also provided.
- the kits will typically include a V H H monoclonal antibody or antigen binding fragment that specifically binds canine PD-1, a specific antibody, and/or a conjugate thereof.
- kits More than one of the VHH monoclonal antibodies, antigen binding fragments, bispecific antibodies, nucleic acid molecule, or vectors can be included in the kit.
- the kit can include two or more V H H monoclonal antibodies that specifically bind canine PD-1, antigen binding fragments that specifically binds canine PD-1, conjugates thereof, bispecific antibodies, or a combination of these molecules.
- the kit can also include components for expression in host cells, such as vectors encoding the V H H monoclonal antibody or antigen binding fragment thereof.
- the kit can include a container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, etc.
- the containers may be formed from a variety of materials such as glass or plastic.
- the container typically holds a composition including one or more of the disclosed canine PD-1-specific V H H monoclonal antibodies, antigen binding fragments, bispecific antibodies or conjugates.
- the container may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- a label or package insert indicates that the composition is used for treating the particular condition.
- the label or package insert typically will further include instructions for use, for example, in a method of increasing cytotoxic T cell activity, or treating a tumor.
- the package insert typically includes instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
- the instructional materials may be written, in an electronic form (such as a computer diskette or compact disk) or may be visual (such as video files).
- the kits may also include additional components to facilitate the particular application for which the kit is designed.
- the kit may additionally contain means of detecting a label (such as enzyme substrates for enzymatic labels, filter sets to detect fluorescent labels, appropriate secondary labels such as a secondary antibody, or the like).
- the kits may additionally include buffers and other reagents routinely used for the practice of a particular method. Such kits and appropriate contents are well known to those of skill in the art.
- Nanobodies are small antibody-like molecules (2.5 nm in diameter, and 4.2 nm in length), with a molecular weight of 12-15 kD, which is >10 times smaller than monoclonal antibodies (Arbabi-Gharhroudi, Historical Perspective and Future Outlook. Front Immunol, 2017. 8: p. 1589). Derived from a Heavy Chain-only form of an antibody and naturally produce by camelids (alpaca, llamas and camels) and cartilaginous fishes, nanobodies as a peptide chain of ⁇ 110 amino acids exhibit similar target affinity and drug-like targeting properties as monoclonal antibodies (MAbs) (Muyldermans, Nanobodies: natural single-domain antibodies. Annu Rev Biochem, 2013.
- Nanobodies are synthesized as only a single heavy chain variable domain (V H H) with three complementarity determining regions (CDRs) that make up the epitope binding portion of the structure. In addition to being small, nanobodies have superior solubility, permeability of tissues and tumors, short plasma half-life and renal elimination (Kijanka et al., Nanomedicine (Lond), 2015. 10(1): p. 161-74; Hassanzadeh-Ghassabeh, et al., Nanomedicine (Lond), 2013. 8(6): p. 1013-26; Sheridan, C., Nat Biotechnol, 2017. 35(12): p.
- nanobodies are less immunogenic and will not trigger complement mediated cytotoxicity (Jovcevska and Muyldermans, BioDrugs, 2020. 34(1): p. 11-26; Brahmer, et al., J Clin Oncol, 2010. 28(19): p. 3167-75; Dahan, et al., Cancer Cell, 2015. 28(3): p. 285-95).
- Antigen-specific immunization of a camelid with a canine PD-1 was used.
- the vaccination regimen was followed by the construction and antigen selection of a phage display library, that allowed isolation of several individual anti-canine PD-1 reactive phage clones.
- the nanobody sequences were determined and subcloned to produce recombinant nanobody and analyzed for specificity and affinity to bind to Canine PD-1 protein and inhibition of PD-1 binding to canine PD-L1.
- canine PD-1 protein was derived from a cultured COS cell line transfected with a canine PD-1 construct. Sero-conversion and nanobody positivity of the animal's response was confirmed by Western blot reactivity to purified canine PD1 protein compared to pre-immune sera (see FIG. 1 ).
- phage display library was constructed and used to isolate M13 derivative phage clones expressing recombinant nanobody protein fused to the pelB-leader sequence and the pIII tail protein (Hassanzadeh, E et. al, 2010 Antibody Engineering Vol. 2 pp 251-266, Springer-Verlag Berlin Heidelberg R. Kontermann and S. Dubel (eds)). Lymphocytes were isolated from blood taken three days after the final immunization and RNA purified (Qiagen). RNA was converted to double stranded complementary DNA (ds cDNA) and amplified in two rounds of polymerase chain reaction (PCR) with gel size selection and purification steps in between each PCR.
- ds cDNA double stranded complementary DNA
- PCR polymerase chain reaction
- PD-1 binding phage were selected either by: 1) bio-panning on PD-1 expressing COS cells after a round subtractive panning on regular COS cells; and/or 2) three rounds of selection on recombinant canine PD-1 protein coated culture wells.
- the resulting phagemid encoded sequences were isolated as individual clones and sequenced to determine the single domain antibody (nanobody) protein sequences. At least 30 individual clones were identified and binding to canine PD-1 protein verified and ranked via ELISA binding activity.
- High activity binders were converted to G-block sequences with optimized codons for bacterial expression and cloned into a pET28 protein expression vector and transformed into BL21 for production and purification of recombinant nanobody protein.
- High affinity PD-1 binding clones (Kd ⁇ 10 nanomolar as calculated via ELISA method, Bobrovnik, J. Biochem Biophys Methods. 30; 57(3): p. 213-36) were tested to determine the capacity to block binding of PD-1 to its cognate-ligand recombinant canine PD-L1 ( FIG. 2 , TABLE 1). Briefly, biotin or nickel coated wells were coated with streptavidin- or His-tagged canine PD-1, respectively, to ensure effective binding. After washing and adding a 2% milk solution to reduce background, candidate nanobodies against canine PD-1 were placed in the wells at various concentrations.
- PD-L1 blocking assay an equal amount of PD-L1 protein was also added to the well. Detection of candidate nanobody PD-1 binding or blockade of PD-L1 was carried out using antibodies specific for nanobodies or canine PD-L1, respectively. A colorimetric assay with a peroxidase-based enzyme determined candidate nanobody binding affinity to canine PD-1 and blockade of PD-L1 interactions with PD-1. A nonspecific nanobody was included in the assays as a control.
- V H H monoclonal antibodies demonstrated binding to canine PD-1 protein. However, only five of the nanobodies had a Kd of less than 10 nM, see the table below. Some V H H monoclonal antibodies were not conclusive as to the binding affinity as they exhibited low expression efficiencies. The following data was obtained.
- the detection of anti-PD-1 V H H monoclonal antibody binding to cellular PD-1 is accomplished by using canine PD-1-expressing COS cells. Briefly, a COS cell line was generated by transfecting the full-length canine PD-1 gene. The PD-1-expressing COS cells are incubated with various concentrations of the V H H monoclonal antibody (0.2-2.0 micrograms) and then anti-camelid/nb antibodies are added, followed by a fluorescent secondary antibody. The cells are interrogated by flow cytometry and PD-1 binding is determined by fluorescence intensity.
- anti-PD-1 V H H monoclonal antibody-mediated blockade of PD-L1 binding to cellular PD-1 is preformed by adding both anti-PD-1 V H H monoclonal antibody and recombinant canine PD-L1-human IgG fusion protein to canine PD-1-expressing COS cells, previously described. Detection of bound canine PD-L1 is assessed by flow cytometry following incubation with a fluorescent secondary antibody specific to human IgG. Blockade is determined by a decrease in fluorescence intensity.
- Dogs are selected who have been diagnosed with one or more of an a osteosarcoma, a hemangiosarcoma, a soft tissue sarcoma (fibrosarcoma, peripheral nerve a sheath tumor (eyomyosarcoma, rhabdomayosarcoma, a lymphangiosarcoma, a synovial cell sarcoma, or a myxosarcoma), a head and neck squamous cell carcinoma, a salivary adenocarcinoma, a gastric adenocarcinoma, an intestinal adenocarcinoma, a pancreatic adenocarcinoma, a hepatocellular adenocarcinoma, a biliary carcinoma, a lung adenocarcinoma, a mammary adenocarcinoma, a transitional cell carcinoma, a prostatic carcinoma, melanoma, a histiocy
- Dogs are selected for treatment based on samples obtained as tissue biopsies for immunohistochemistry or needle aspirates of the malignant tissues for flow cytometry evaluation. Tissues are then assayed to assess the proportion of PD-L1 expression on the malignant cells surface and the PD1 expression on the tumor or circulating lymphocytes.
- Complete blood account (CBC) and blood serum chemistry and urine analysis is obtained as a base line prior to each treatment and seven to ten days after the treatment.
- V H H monoclonal antibodies is/are administered intravenous in a dose of 1 ⁇ g-10 mg/kg over 30 minutes once every three weeks as long as there is a clinical response and there are no limiting toxicities.
- the composition is administered intra lesional, intrathecal, or intravesical.
- a method of phage display selection with a library derived from a PD-1 hyperimmunized alpaca was used to isolate thirty individual canine PD-1 reactive phage clones.
- the nanobody sequences were determined and subcloned to produce individual recombinant nanobodies. Each were analyzed for specificity and affinity to canine PD-1 protein as determined via an enzyme-linked immunosorbent assay (ELISA), see FIG. 4 .
- ELISA enzyme-linked immunosorbent assay
- V H H Five nanobodies (V H H), based on affinity for PD-1 binding are shown in TABLE 2. Also measured was the ability of each V H H clone to sterically inhibit canine PD-1 from binding to canine PD-L1, shown as the concentration of nanobody needed to produce a 50% inhibition
- Activity ranging from 5 to ⁇ 10 nanomolar demonstrates functional efficacy as a PD-1 checkpoint inhibitor and thus usefulness for the treatment of canine cancer.
- a 25 kg dog requires a dose of 3.5 mg/kg to obtain a theoretical therapeutic inhibition of PD-1/PDL-1. Therefore, approximately 1 gram of drug product would be required over a 2-week course of treatment.
- Bivalency a property of an antibody to bind two sites (epitopes) on a ligand, will increase the strength of binding through a characteristic in immunology termed avidity (see FIG. 5 ).
- avidity a characteristic in immunology termed avidity (see FIG. 5 ).
- a “bi-epitope binding” version also referred as a “diabody” is tested. This is achieved by linking two nano-bodies together with a polypeptide. The binding and blocking activity of these diabody bi-epitope linked antibody pairs is measured using optical biosensor binding assays and in vitro PD-1/PD-1.1 inhibition assays. The following combinations are ranked by highest to lowest blocking activity and functional avidity:
- Small size and a long serum half-life are two important features for therapeutic applications of biologics.
- the resident plasma half-life of small protein can be significantly increased by linking to albumin or small peptide domains that bind albumin.
- the linking peptide can provide additional steric blocking activity of PD1/PDL-1 interaction increasing the functional efficacy of the drug.
- functional benefits from the diabody can lengthen the duration needed between treatments and the amount of drug required for each treatment, thus lowering the cost of a treatment course.
- the two different linking strategies use either the larger canine albumin protein or smaller albumin binding peptide domain.
- Cellular Binding and Functional Effects of PD-1 nanobody The detection of PD-1 V H H (also called nanobody (nb)) or diabody (PD-1 nb/db) binding to cellular PD-1 is accomplished by using canine PD-1-expressing COS cells.
- a COS cell line was generated by transfecting the full-length canine PD-1 gene.
- the PD-1-expressing COS cells are incubated with various concentrations of the PD-1 nb/db (0.2-2.0 micrograms) and then anti-camelid/nb antibodies are added, followed by a fluorescent secondary antibody.
- the cells are interrogated by flow cytometry and PD-1 nb/db binding determined by fluorescence intensity.
- the determination of PD-1 nb/db-mediated blockade of PD-L1 binding to cellular PD-1 is completed by adding both PD-1 nb/db and recombinant canine PD-L1-human IgG fusion protein to canine PD-1-expressing COS cells.
- Detection of bound canine PD-L1 is assessed by flow cytometry following incubation with a fluorescent secondary antibody specific to human IgG. Blockade is determined by a decrease in fluorescence intensity.
- canine T-cells Functional effects of canine PD-1 blockade by PD-1 nb/db is assessed on canine T-cells (Coy et al., Vet Comp Oncol, 2017. 15(4): p. 1487-1502). Briefly, isolated T-cells from canine blood are activated using the stimulant Concanavalin A. To these cells various mixtures of PD-1 nb and recombinant canine PD-L1 are added and the cells incubated for up to 4 days. Supernatants are collected and assayed for the determination of release of IFN-gamma, by ELISA.
- G-block synthesis was carried out to insert the sequences into a pPICZ ⁇ vector.
- Yeast clones with multiple recombinant genome insertions of the nanobody expression cassette were selected by plating onto increasing amounts of Zeocin antibiotic containing YPDS (yeast extract peptone dextrose) agar plates. Clones were confirmed by RT-PCR screening and nanobody protein production (Protein assay and Coomassie stain SDS-PAGE). Large scale production is done by creating a large biomass of a specific clone grown for 48 hours in a 1 liter shaker culture of Buffered Glycerol Minimal Media containing Histidine.
- the pharmacokinetics and tolerability are tested for two individual paired nanobodies targeting two epitopes on canine PD-1, in comparison to the same nanobodies linked by a pseudo albumin linker in one to one ratio (diabody).
- the study includes 6 male hound dogs, set in two cohorts of three dogs each. Each dog receives a single IV doses of 0.3, 3, or 30 mg/kg of the paired nanobody or the diabody based on their assigned cohort. Changes in body weight, clinical signs, and changes in clinical pathology parameters will be assessed over a period of two weeks after each injection for a total of 49 days (study days-7-42).
- Procedures and sample collection All the dogs are managed in accordance with approved animal care and procedural testing guidelines. The dogs are monitored throughout the study period on study days ⁇ 7, and 1-42 with daily physical examinations, occasional blood pressure measurements, blood works, and urine analysis. Four ml of blood are collected for complete blood count (CBC) and serum biochemistry tests (EDTA tube and additive free tube correspondently) on days ⁇ 7, 1 (prior to injection) and on days 2, 3, 4, 5, 6, 7 and 14.
- CBC complete blood count
- EDTA tube and additive free tube correspondently on days ⁇ 7, 1 (prior to injection) and on days 2, 3, 4, 5, 6, 7 and 14.
- PK analysis 6 ml of whole blood is collected in serological tube (additive free tube) and is allowed to clot at room temperature for 30 minutes followed by centrifugation (1500 g for 5 min) and separation of the supernatant serum to cryovial tubes.
- the serum is than stored in ⁇ 80° C. until analysis.
- Baseline samples are collected on study day ⁇ 7 followed by collection on study day 1, prior to injection, every 15 min for the first hour, and on hours 1, 2, 4, 8, and 12 hours after injection (total of 54 ml over the period of 24 hours).
- follow up samples for PK analysis are also collected on study days 2, 3, 4, 5, 6, and 7 and 14. This protocol is repeated three times for each of the three dosages, excluding day-7 routine which is done only prior to the first injection.
- the animals are considered “off-study” the presence and concentration of the 4b4 nanobody is detected by liquid chromatography-mass spectrometry (LC-MS). The pharmacokinetic data is analyzed and compared between the two cohorts.
- LC-MS liquid chromatography-mass spectrometry
- Drug preparation and handling The formulations are prepared and stored under aseptic conditions, the bi-epitope nanobody pair mixture and Diabody link compounds are suspended in sterile saline at the concentration of 250 mg/ml. This solution is filtered through a 0.2 ⁇ m membrane to a sterile vial and stored in ⁇ 20° C. The catheter placement and administration follow the guidelines for the administration of IV drugs.
- the raw data derived from the blood chemistry and plasma levels of drug product is used to determine any dose dependent toxicological indications and effects of the proposed modification on plasma half-life, Cmax, exposure and indications of distribution.
Abstract
Description
QVQLQASGGGLVQPGGSLTLSCAASG WYRQGPGKQREFVA | |
YADSAKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNA WGQGTQVG |
SEQ ID NO: 2 is the amino acid sequence of the CDR1 of NAN4 (5A1).
SEQ ID NO: 3 is the amino acid sequence of the CDR2 of NAN4 (5A1).
SEQ ID NO: 4 is the amino acid sequence of the CDR3 of NAN4 (5A1).
SEQ ID NO: 5 is the amino acid sequence of a VHH domain of NAN7/8 (5A5).
QVQLQASGGGLVEPGGSLRLSCAASG WYRQAPGKERELVA | |
YADSVKGRFTISRDNAKNTAYLQMDSLKAEDTGVYYCNA WGQGTQVG |
SEQ ID NO: 6 is the amino acid sequence of the CDR1 of NAN7/8 (5A5).
SEQ ID NO: 7 is the amino acid sequence of the CDR2 of NAN7/8 (5A5).
SEQ ID NO: 8 is the amino acid sequence of the CDR3 of NAN7/8 (5A5).
SEQ ID NO: 9 is the amino acid sequence of a VHH domain of NAN10 (4B4).
QVQLQASGGGLVQGGESLRLSCAASG WYRQAPGKEREFVA | |
YLDSVKGRFTISRDNTKDTVYLQMNTLKPEDTAVYYCNA WGQGTQVG |
SEQ ID NO: 10 is the amino acid sequence of the CDR1 of NAN10 (4B4).
SEQ ID NO: 11 is the amino acid sequence of the CDR2 of NAN10 (4B4).
SEQ ID NO: 12 is the amino acid sequence of the CDR3 of NAN10 (4B4).
SEQ ID NO: 13 is the amino acid sequence of a VHH domain of NAN15 (4B2).
QVQLQASGGGLVQPGEHLLLSCAASG WYRQAPGKEREKVA | |
YADSVKGRFTISRENAKNTLYLQMNSLKPEDTALYFCAK WGQGTQVG |
SEQ ID NO: 14 is the amino acid sequence of the CDR1 of NAN15 (4B2).
SEQ ID NO: 15 is the amino acid sequence of the CDR2 of NAN15 (4B2).
SEQ ID NO: 16 is the amino acid sequence of the CDR3 of NAN15 (4B2).
SEQ ID NO: 17 is the amino acid sequence of a VHH domain of NAN28(1B5).
QVQLVQASGGGLVQPGGSLRLSCAAS WVRQAPGKGLEWVA | |
YADSVKGRFTISRDNTKNTVYLQMNNLKPEDTAVYYCNA WGQGTQVG |
SEQ ID NO: 18 is the amino acid sequence of the CDR1 of NAN28(1B5).
SEQ ID NO: 19 is the amino acid sequence of the CDR2 of NAN28(1B5).
SEQ ID NO: 20 is the amino acid sequence of the CDR3 of NAN28(1B5).
The following sequences are shown in
SEQ ID NO: 21 is the amino acid sequence of a VHH domain of
SEQ ID NOs: 22, 23, and 24 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN1, respectively.
SEQ ID NO: 25 is the amino acid sequence of a VHH domain of NAN 2.
SEQ ID NOs: 26, 27, and 28 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN2, respectively.
SEQ ID NO: 29 is the amino acid sequence of a VHH domain of NAN3.
SEQ ID NOs: 30, 31 and 32 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN3, respectively.
SEQ ID NO: 33 is the amino acid sequence of a VHH domain of NAN5.
SEQ ID NOs: 34, 35 and 36 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN5, respectively.
SEQ ID NO: 37 is the amino acid sequence of a VHH domain of NAN6.
SEQ ID NOs: 38, 39 and 40 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN6, respectively.
SEQ ID NO: 41 is the amino acid sequence of a VHH domain of NAN5.
SEQ ID NOs: 42, 43 and 44 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN9, respectively.
SEQ ID NO: 45 is the amino acid sequence of a VHH domain of NAN11.
SEQ ID NOs: 46, 47 and 48 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN11, respectively.
SEQ ID NO: 49 is the amino acid sequence of a VHH domain of NAN12.
SEQ ID NOs: 50, 51 and 52 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN12, respectively.
SEQ ID NO: 53 is the amino acid sequence of a VHH domain of NAN13.
SEQ ID NOs: 54, 55 and 56 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN13, respectively.
SEQ ID NO: 57 is the amino acid sequence of a VHH domain of NAN14.
SEQ ID NOs: 58, 59 and 60 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN14, respectively.
SEQ ID NO: 61 is the amino acid sequence of a VHH domain of NAN16.
SEQ ID NOs: 62, 63 and 64 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN16, respectively.
SEQ ID NO: 65 is the amino acid sequence of a VHH domain of NAN17.
SEQ ID NOs: 66, 67, and 68 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN17, respectively.
SEQ ID NO: 69 is the amino acid sequence of a VHH domain of NAN18.
SEQ ID NOs: 70, 71 and 72 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN18, respectively.
SEQ ID NO: 73 is the amino acid sequence of a VHH domain of NAN19.
SEQ ID NOs: 74, 75 and 76 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN19, respectively.
SEQ ID NO: 77 is the amino acid sequence of a VHH domain of NAN20.
SEQ ID NOs: 78, 79 and 80 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN20, respectively.
SEQ ID NO: 81 is the amino acid sequence of a VHH domain of NAN21.
SEQ ID NOs: 82, 83, 84 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN21, respectively.
SEQ ID NO: 85 is the amino acid sequence of a VHH domain of NAN22.
SEQ ID NOs: 86, 87, and 88 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN22, respectively.
SEQ ID NO: 89 is the amino acid sequence of a VHH domain of NAN23.
SEQ ID NOs: 90, 91 and 92 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN23, respectively.
SEQ ID NO: 93 is the amino acid sequence of a VHH domain of NAN24.
SEQ ID NOs: 94, 95, 96 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN24, respectively.
SEQ ID NO: 97 is the amino acid sequence of a VHH domain of NAN25.
SEQ ID NOs: 98, 99 and 100 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN25, respectively.
SEQ ID NO: 101 is the amino acid sequence of a VHH domain of NAN26.
SEQ ID NOs: 102, 103, and 104 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN26, respectively.
SEQ ID NO: 105 is the amino acid sequence of a VHH domain of NAN27.
SEQ ID NOs: 106, 107 and 108 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN27, respectively.
SEQ ID NO: 109 is the amino acid sequence of a VHH domain of NAN29.
SEQ ID NOs: 110, 111 and 112 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN29, respectively.
SEQ ID NO: 113 is the amino acid sequence of a VHH domain of NAN30.
SEQ ID NOs: 114, 115 and 116 are the amino acid sequences of a CDR1, CDR2, and CDR3 of NAN30, respectively.
SEQ ID NOs: 117-119 are consensus sequences of a VHH domain of a monoclonal antibody that specifically binds canine PD-1.
Tumor | Tumor Antigens |
Acute myelogenous leukemia | Wilms tumor 1 (WT1), preferentially |
expressed antigen of melanoma | |
(PRAME), PR1, proteinase 3, | |
elastase, cathepsin G | |
Chronic myelogenous leukemia | WT1, PRAME, PR1, proteinase 3, |
elastase, cathepsin G | |
Myelodysplastic syndrome | WT1, PRAME, PR1, proteinase 3, |
elastase, cathepsin G | |
Acute lymphoblastic leukemia | PRAME |
Chronic lymphocytic leukemia | Survivin |
Non-Hodgkin's lymphoma | Survivin |
Multiple myeloma | New York esophageous 1 (NY-Eso1) |
Malignant melanoma | MAGE, MART, Tyrosinase, PRAME, |
GP100 | |
Breast cancer | WT1, herceptin |
Lung cancer | WT1 |
Prostate cancer | Prostate-specific antigen (PSA) |
Colon cancer | Carcinoembryonic antigen (CEA) |
Renal cell carcinoma (RCC) | Fibroblast growth factor 5 (FGF-5) |
-
- 1) Alanine (A), Serine (S), Threonine (T);
- 2) Aspartic acid (D), Glutamic acid (E);
- 3) Asparagine (N), Glutamine (Q);
- 4) Arginine (R), Lysine (K);
- 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and
- 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).
TABLE 1 | ||||
Protein | ||||
Fusion Protein | Expression for | Binding | Blocking | |
Sequence | Binds to PD-1 | Affinity Testing | Affinity Kd (M) | (50% inhibition) |
NAN1 | + | Insufficient | TBD | TBD |
NAN2 | + | Insufficient | TBD | TBD |
NAN3 | + | Insufficient | TBD | TBD |
NAN4 | + | Sufficient | 7.00 × 10−9 | 8.25 × 10−9 M |
NAN5 | + | Insufficient | TBD | TBD |
NAN6 | + | Sufficient | >10 × 10−9 * | TBD |
NAN7/8 | + | Sufficient | 5.01 × 10−9 | 6.83 × 10−9 M |
NAN9 | + | Sufficient | >10 × 10−9 * | TBD |
NAN10 | + | Sufficient | 2.30 × 10−9 | 5.04 × 10−9 M |
NAN11 | + | Insufficient | TBD | TBD |
NAN12 | + | Insufficient | TBD | TBD |
NAN13/14 | + | Sufficient | >10 × 10−9 * | TBD |
NAN15 | + | Sufficient | 2.51 × 10−9 | 5.0 × 10−9 M |
NAN16 | + | Insufficient | TBD | TBD |
NAN17/24 | + | Insufficient | TBD | TBD |
NAN18 | + | Insufficient | TBD | TBD |
NAN19 | + | Insufficient | TBD | TBD |
NAN20 | + | Sufficient | >10 × 10−9 * | TBD |
NAN21 | + | Insufficient | TBD | TBD |
NAN22 | + | Insufficient | >10 × 10−9 * | TBD |
NAN23 | + | Insufficient | TBD | TBD |
NAN25 | + | Insufficient | TBD | TBD |
NAN26 | + | Insufficient | TBD | TBD |
NAN27 | + | Sufficient | >10 × 10−9 * | TBD |
NAN28 | + | Sufficient | 0.95 × 10−9 | 9.4 × 10−9 M |
NAN29 | + | Insufficient | TBD | TBD |
NAN30 | + | Insufficient | TBD | TBD |
* Predicted affinity, not quantitatively measured. | ||||
TBD—To Be Determined, further testing required |
TABLE 2 | ||
Clone | Affinity Kd (M) × 10−9 | 50% Inhibition (M) × 10−9 |
1B5 | 0.95 | 0.9 |
4B4 | 2.30 | 5.04 |
4B2 | 2.51 | 5.0 |
5A5 | 5.01 | 6.83 |
5A1 | 7.00 | 8.25 |
TABLE 3 | |||
Combination | Functional Ranking | ||
4B2 + |
1 | ||
4B2 + 5A5 | 2 | ||
4B4 + 5A5 | 3 | ||
4B2 + 5A1 | 4 | ||
4B4 + 5Al | 5 | ||
4B2 + 1B5 | 6 | ||
4B4 + 1B5 | 7 | ||
5A1 + |
8 | ||
5A5 + 1B5 | 9 | ||
5A1 + |
10 | ||
Claims (20)
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